Process for producing either optically active n-substituted beta-amino acid and optically active n-substituted beta-amino acid ester or optically active n-substituted 2-homopipecolic acid and optically active n-substituted 2-homopipecolic acid ester

ABSTRACT

The present invention discloses a process which comprises selectively hydrolyzing one enantiomer of racemic mixtures of an N-substituted β-amino acid alkyl ester or N-substituted 2-homopipecolic acid ester represented by the formula (I):  
                 
         wherein Ar, R 1 , R 2 , R 3 , R 4  and R 5  are the same as defined in the specification, 
 
in the presence of a hydrolase to form an optically active ((R) or (S))-N-substituted-β-amino acid or optically active ((R) or (S))-N-substituted 2-homopipecolic acid represented by the formula (II):  
                 
 
and simultaneously to obtain an unreacted optically active ((S) or (R))-N-substituted β-amino acid alkyl ester or unreacted optically active ((S) or (R))-N-substituted 2-homopipecolic acid ester represented by the formula (III):  
                 
which has a reverse steric absolute configuration to that of the compound represented by the formula (II).

TECHNICAL FIELD

The present invention relates to a process for preparing either anoptically active ((R) or (S))-N-substituted β-amino acid and anoptically active ((S) or (R))-N-substituted β-amino acid alkyl ester oran optically active ((R) or (S))-N-substituted 2-homopipecolic acid andan optically active ((S) or (R))-N-substituted 2-homopipecolic acidester, simultaneously, from an N-substituted β-amino acid alkyl ester oran N-substituted 2-homopipecolic acid ester (racemic mixture).

Of these, the optically active N-substituted β-amino acid and an esterthereof can be easily introduced into an optically active β-amino acidand an ester thereof which is useful as a synthetic intermediate for aphysiologically active peptide or a lactam type antibiotic according tothe conventionally known reducing method (for example, Current MedicinalChemistry, 6, 955 (1999)). Also, of these, the optically activeN-substituted 2-homopipecolic acid and an ester thereof can be easilyintroduced into an optically active 2-homopipecolic acid and an esterthereof which is useful as a synthetic intermediate for a medicineaccording to the conventionally known reducing method (mentioned inExample 14 below).

BACKGROUND ART

In the prior art, as a method for preparing optically active ((R) or(S))-β-amino acids and optically active ((S) or (R))-β-amino acid esterssimultaneously from β-amino acid esters (racemic mixture) by using ahydrolase, it has been disclosed a method in which one of enantiomers ofethyl 3-benzyloxycarbonylaminobutanoate (racemic mixture) is selectivelyhydrolyzed in 1,4-dioxane to obtain an optically active3-(S)-aminobutanoic acid ethyl ester and an optically active3-(R)-aminobutanoic acid in the presence of a lipase originated fromCandida antarctica, water and triethylamine (Tetrahedron Asymmetry, 8,37 (1997)).

However, according to this method, there are problems that a reactiontime is quite long, an equal amount of triethylamine to the substratemust be added as a third component to heighten optical purity of theobject, and the like, and it is disadvantageous as an industrialpreparation method.

Also, there is no description about hydrolysis of β-amino acid alkylesters in which a substituent on a nitrogen atom is an aralkyl groupaccording to the present invention.

Moreover, in the prior art, as a method for preparing an opticallyactive ((R) or (S))-N-substituted 2-homopipecolic acid and an opticallyactive ((S) or (R))-N-substituted 2-homopipecolic acid estersimultaneously from an N-substituted 2-homopipecolic acid ester (racemicmixture) by using a hydrolase, it has been disclosed a method in whichone of enantiomers of methyl N-acetyl-2-homopipecolate (racemic mixture)is selectively hydrolyzed in the presence of a Pig liver esterase toobtain an optically active ((R) or (S))-N-acetyl-2-homopipecolic acidand an optically active ((S) or (R))-N-acetyl-2-homopipecolic acid ester(Can. J. Chem., 65, 2722 (1987)).

However, according to this method, there are problems that an amount ofthe hydrolase to be used is extremely large, optical purity of theobjective material is low, and the like, and it is disadvantageous as anindustrial preparation method.

An object of the present invention is to solve the above-mentionedproblems and to provide a process for preparing an optically activeβ-amino acid and an optically active β-amino acid ester that isindustrially advantageous in which an optically active ((R) or(S))-N-substituted β-amino acid and an optically active ((S) or(R))-N-substituted β-amino acid alkyl ester are obtained simultaneouslywith high yield and high selectivity from an N-substituted β-amino acidalkyl ester (racemic mixture) according to a simple and easy method.

Another object of the present invention is to solve the above-mentionedproblems and to provide a process for preparing an optically activehomopipecolic acid and an optically active homopipecolic acid ester thatis industrially suitable in which an optically active ((R) or(S))-N-substituted 2-homopipecolic acid and an optically active ((S) or(R))-N-substituted 2-homopipecolic acid ester are obtainedsimultaneously with high yield and high selectivity from anN-substituted 2-homopipecolic acid ester (racemic mixture).

SUMMARY OF THE INVENTION

An object of the present invention can be solved by a process forpreparing an optically active N-substituted β-amino acid and anoptically active N-substituted β-amino acid ester, or an opticallyactive N-substituted 2-homopipecolic acid and an optically activeN-substituted 2-homopipecolic acid ester which comprises selectivelyhydrolyzing an enantiomer of an N-substituted β-amino acid alkyl esteror an N-substituted 2-homopipecolic acid ester (racemic mixture)represented by the formula (I):

-   -   wherein Ar represents a substituted or unsubstituted aryl group,        R¹ represents a substituted or unsubstituted alkyl group, an        alkenyl group, a substituted or unsubstituted aralkyl group or a        substituted or unsubstituted aryl group, R² represents a        hydrogen atom, R³ and R⁴ each independently represent a hydrogen        atom, a substituted or unsubstituted alkyl group or a        substituted or unsubstituted aryl group, R⁵ represents a        substituted or unsubstituted alkyl group, and R¹ and R² may form        a ring by bonding to each other,        in the presence of a hydrolase to form an optically active ((R)        or (S))-N-substituted β-amino acid or an optically active ((R)        or (S))-N-substituted 2-homopipecolic acid represented by the        formula (II):    -   wherein Ar, R¹, R², R³ and R⁴ have the same meanings as defined        above,        and simultaneously to obtain an optically active ((S) or        (R))-N-substituted β-amino acid alkyl ester or an optically        active ((S) or (R))-N-substituted 2-homopipecolic acid ester        (incidentally, it has a reverse steric absolute configration to        that of the compound represented by the formula (II).)        represented by the formula (III):    -   wherein Ar, R¹, R², R³, R⁴ and R⁵ have the same meanings as        defined above.

BEST MODE FOR CARRYING OUT THE INVENTION

In the preparation processes of the present inventtion, an N-substitutedβ-amino acid alkyl ester represented by the following formula (I-a):

-   -   wherein Ar, R¹, R², R³, R⁴ and R⁵ have the same meanings as        defined above,        or an N-substituted 2-homopipecolic acid ester represented by        the following formula (I-b):    -   wherein Ar, R³, R⁴ and R⁵ have the same meanings as defined        above,        is used as a representative compound.

In the hydrolysis reaction of the present invention, for example, asshown by the following reaction scheme:

-   -   wherein Ar, R¹, R², R³ and R⁴ have the same meanings as defined        above. Incidentally, (II) and (III) have the reverse steric        absolute configration to each other,        one enantiomer of the racemic mixture (hereinafter sometimes        referred to as Compound (I).) of the N-substituted β-amino acid        alkyl ester or the N-substituted 2-homopipecolic acid ester        represented by the above-mentioned formula (I) is selectively        hydrolyzed in the presence of a hydrolase to form an optically        active ((R) or (S))-N-substituted β-amino acid or an optically        active ((R) or (S))-N-substituted 2-homopipecolic acid ester        (hereinafter sometimes referred to as Compound (II).)        represented by the formula (II), and simultaneously to obtain an        unreacted optically active ((S) or (R))-N-substituted β-amino        acid alkyl ester or optically active ((S) or (R))-N-substituted        2-homopipecolic acid ester (hereinafter sometimes referred to as        Compound (III).) represented by the formula (III). Incidentally,        Compound (II) and Compound (III) have reverse steric absolute        configration to each other.

When the N-substituted β-amino acid alkyl ester represented by theabove-mentioned formula (I-a) is used, an optically active ((R) or(S))-N-substituted β-amino acid and an optically active ((S) or(R))-N-substituted β-amino acid alkyl ester represented by the followingformulae (II-a) and (III-a):

-   -   wherein Ar, R¹, R³, R⁴ and R⁵ have the same meanings as defined        above,        can be obtained, and when the N-substituted 2-homopipecolic acid        ester represented by the above-mentioned formula (I-b) is used,        an optically active ((R) or (S))-N-substituted 2-homopipecolic        acid and an optically active ((S) or (R))-N-substituted        2-homopipecolic acid ester represented by the following formulae        (II-b) and (III-b):    -   wherein Ar, R³, R⁴ and R⁵ have the same meanings as defined        above,        can be obtained.

Incidentally, in the above-mentioned formulae (II-a) and (III-a), it isparticularly preferred that the optically active ((R) or(S))-N-substituted β-amino acid represented by the formula (II-a) is anoptically active N-substituted β-amino acid represented by the formula(IV-a):

-   -   wherein Ar, R³ and R⁴ have the same meanings as defined above,        and the unreacted optically active ((S) or (R))-N-substituted        2-β-amino acid ester is an optically active N-substituted        β-amino acid ester represented by the formula (V-a):    -   wherein Ar, R³, R⁴ and R⁵ have the same meanings as defined        above.

Also, in the above-mentioned formulae (II-b) and (III-b), it isparticularly preferred that the optically active ((R) or(S))-N-substituted 2-homopipecolic acid represented by the formula(II-b) is an optically active (R)-N-substituted 2-homopipecolic acidrepresented by the formula (IV-b):

-   -   wherein Ar, R³ and R⁴ have the same meanings as defined above,        and an unreacted optically active ((S) or (R))-N-substituted        2-homopipecolic acid ester is an optically active        (S)-N-substituted 2-homopipecolic acid ester represented by the        formula (V-b):    -   wherein Ar, R³, R⁴ and R⁵ have the same meanings as defined        above.

In the following, the respective substituents of the compounds of thepresent invention are explained.

Ar in Compound (I) represents a substituted or unsubstituted aryl group.

The above-mentioned substituted or unsubstituted aryl group is (1) “anaryl group having no substituent” or (2) “an aryl group having asubstituent(s)”. As “the aryl group having no substituent” of (1), theremay be specifically mentioned an aryl group such as a phenyl group, anaphthyl group, an anthryl group, etc. (incidentally, these groupsinclude various kinds of isomers), preferably a phenyl group, a1-naphthyl group, a 2-naphthyl group. As the substituent(s) for “thearyl group having a substituent(s)” of (2), there may be mentioned, forexample, an alkyl group having 1 to 4 carbon atoms such as a methylgroup, an ethyl group, a propyl group, a butyl group (incidentally,these groups include various kinds of isomers); a hydroxyl group; ahalogen atom such as a fluorine atom, a chlorine atom, a bromine atom,an iodine atom, etc.; an alkoxy group having 1 to 4 carbon atoms such asa methoxy group, an ethoxy group, a propoxy group, a butoxy group, etc.(incidentally, these groups include various kinds of isomers); a nitrogroup, etc. As the aryl group having such a substituent(s), there may bespecifically mentioned a 2-tolyl group, a 3-tolyl group, a 4-tolylgroup, a 2,3-xylyl group, a 2,6-xylyl group, a 2,4-xylyl group, a3,4-xylyl group, a mesityl group, a 2-hydroxyphenyl group, a4-hydroxyphenyl group, a 3,4-dihydroxyphenyl group, a 2-fluorophenylgroup, a 4-fluorophenyl group, a 2-chlorophenyl group, a 3-chlorophenylgroup, a 4-chlorophenyl group, a 3,4-dichlorophenyl group, a4-bromophenyl group, a 4-iodophenyl group, a 2-methoxyphenyl group, a3-methoxyphenyl group, a 4-methoxyphenyl group, a 3,4-dimethoxyphenylgroup, a 3,4-methylenedioxyphenyl group, a 4-ethoxyphenyl group, a4-butoxy phenyl group, a 4-isopropoxyphenyl group, a 4-nitrophenylgroup, a 2-nitrophenyl group, etc., preferably a 2-tolyl group, a4-tolyl group, a 2,3-xylyl group, a 3,4-xylyl group, a 4-hydroxyphenylgroup, a 3,4-dihydroxyphenyl group, a 2-fluorophenyl group, a4-fluorophenyl group, a 2-chlorophenyl group, a 4-chlorophenyl group, a3,4-dichlorophenyl group, a 2-methoxyphenyl group, a 4-methoxyphenylgroup, a 3,4-dimethoxyphenyl group, a 3,4-methylenedioxyphenyl group, a4-ethoxyphenyl group, a 4-nitrophenyl group, a 2-nitrophenyl group, morepreferably a 4-tolyl group, a 4-hydroxyphenyl group, a3,4-dihydroxyphenyl group, a 4-fluorophenyl group, a 4-chlorophenylgroup, a 4-methoxyphenyl group, a 3,4-dimethoxyphenyl group, a3,4-methylenedioxyphenyl group and a 4-nitrophenyl group.

R¹ of Compound (I) represents a substituted or unsubstituted alkylgroup, alkenyl group, a substituted or unsubstituted aralkyl group or asubstituted or unsubstituted aryl group.

The above-mentioned substituted or unsubstituted alkyl group means (3)“an alkyl group having no substituent” or (4) “an aryl group having asubstituent(s)”. As “the alkyl group having no substituent” of (3),there may be mentioned, more specifically, an alkyl group having 1 to 10carbon atoms such as a methyl group, an ethyl group, a propyl group, abutyl group, a pentyl group, a hexyl group, a heptyl group, an octylgroup, a nonyl group, decyl group, etc (incidentally, these groupsinclude various kinds of isomers), preferably a methyl group, an ethylgroup, a n-propyl group, an isopropyl group, a n-butyl group, a n-octylgroup, more preferably a methyl group, an ethyl group. As thesubstituent for (4) “the alkyl group having a substituent(s)”, there maybe mentioned, for example, a halogen atom such as a fluorine atom, achlorine atom, a bromine atom, an iodine atom, etc.; a hydroxyl group;an alkoxyl group having 1 to 4 carbon atoms such as a methoxyl group, anethoxyl group, a propoxyl group, a butoxyl group, etc. (incidentally,these groups include various kinds of isomers); an amino group; adialkylamino group such as a dimethylamino group, a diethylamino group,a dipropylamino group, etc. (incidentally, these groups include variouskinds of isomers); a cyano group; a nitro group, etc., preferably afluorine atom, a chlorine atom, a hydroxyl group, an amino group, adimethylamino group, a diethylamino group, a cyano group. As the alkylgroup having such a substituent, there may be mentioned, morespecifically, a fluoromethyl group, a chloromethyl group, ahydroxymethyl group, a methoxymethyl group, an aminomethyl group, adimethylaminomethyl group, a 2-chloroethyl group, a 2,2-dichloroethylgroup, a 2,2,2-trichloroethyl-group, a 2,2,2-trifluoroethyl group, a2-hydroxyethyl group, a 2-cyanoethyl group, a 2-methoxyethyl group, a2-ethoxyethyl group, a 2-bromoethyl group, a 2-dimethylamino group, a2-chloropropyl group, a 3-chloropropyl group, etc., preferably afluoromethyl group, a chloromethyl group, a hydroxymethyl group, anaminomethyl group, a dimethylaminomethyl group, a 2-chloroethyl group, a2,2,2-trichloroethyl group, a 2,2,2-trifluoroethyl group, and a2-cyanoethyl group.

The above-mentioned alkenyl group of R¹ may be mentioned, specificallyan alkenyl group having 2 to 10 carbon atoms such as a vinyl group, apropenyl group, a butenyl group, a pentenyl group, a hexenyl group, aheptenyl group, an octenyl group, a nonenyl group, a decenyl group, etc.(incidentally, these groups include various kinds of isomers),preferably a vinyl group, a propenyl group, a butenyl group, a pentenylgroup, more preferably a vinyl group, a 1-propenyl group, and a2-propenyl group.

The substituted or unsubstituted aralkyl group of the above-mentioned R¹is (5) “an aralkyl group having no substituent” or (6) “an aralkyl grouphaving a substituent(s)”. “The aralkyl group having no substituent” of(5) may be mentioned, more specifically, an aralkyl group (incidentally,these groups include various kinds of isomers) such as a benzyl group, aphenethyl group, a phenylpropyl group, a phenylbutyl group, etc.,preferably a benzyl group, a 1-phenethyl group, a 2-phenethyl group, a3-phenylpropyl group, a 3-phenylbutyl group. As the substituent for “thearalkyl group having a substituent(s)” of (6), there may be mentioned,for example, an alkyl group having 1 to 10 carbon atoms such as a methylgroup, an ethyl group, a propyl group, a butyl group, a pentyl group, ahexyl group, a heptyl group, an octyl group, a nonyl group, a decylgroup, etc. (incidentally, these groups include various kinds ofisomers); a hydroxyl group; a nitro group; a halogen atom such as afluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.; analkoxy group having 1 to 10 carbon atoms such as a methoxy group, anethoxy group, a propoxy group, a butoxy group, a pentyloxy group, ahexyloxy group, a heptyloxy group, an octyloxy group, a nonyloxy group,a decyloxy group (incidentally, these groups include various kinds ofisomers); an aralkyloxy group having 7 to 10 carbon atoms such as abenzyloxy group, a phenethyloxy group, a phenylpropoxy group(incidentally, these groups include various kinds of isomers); anaryloxy group such as a phenyloxy group, naphthyloxy group, etc.(incidentally, these groups include various kinds of isomers); analkoxyalkoxy group such as a methoxymethoxy group, a methoxyethoxygroup, etc. (incidentally, these groups include various kinds ofisomers); a monoalkylamino group such as a methylamino group, anethylamino group, etc. (incidentally, these groups include various kindsof isomers); a dialkylamino group such as a dimethylamino group, adiethylamino group, etc. (incidentally, these groups include variouskinds of isomers); an acylamino group such as a formylamino group, anacetylamino group, a benzoylamino group, etc. (incidentally, thesegroups include various kinds of isomers), a nitro group, a cyano group,a trifluoromethyl group, and the like. The aralkyl group having such asubstituent(s) may be mentioned, more specifically, a 2-fluorobenzylgroup, a 3-fluorobenzyl group, a 4-fluorobenzyl group, a3,4-difluorobenzyl group, a 2,4-difluorobenzyl group, a 2-chlorobenzylgroup, a 3-chlorobenzyl group, a 4-chlorobenzyl group, a2,4-dichlorobenzyl group, a 3,4-dichlorobenzyl group, a 2-bromobenzylgroup, a 3-bromobenzyl group, a 4-bromobenzyl group, a 2,4-dibromobenzylgroup, a 3,4-dibromobenzyl group, a 2-iodobenzyl group, a 3-iodobenzylgroup, a 4-iodobenzyl group, a 2,3-diiodobenzyl group, a3,4-diiodobenzyl group, a 2-methylbenzyl group, a 3-methylbenzyl group,a 4-methylbenzyl group, a 2-ethylbenzyl group, a 3-ethylbenzyl group, a4-ethylbenzyl group, a 2-hydroxybenzyl group, a 3-hydroxybenzyl group, a4-hydroxybenzyl group, a 2-methoxybenzyl group, a 3-methoxybenzyl group,a 4-methoxybenzyl group, a 2,4-dimethoxybenzyl group, a3,4-dimethoxybenzyl group, a 2-ethoxybenzyl group, a 4-ethoxybenzylgroup, a 2-trifluoromethylbenzyl group, a 4-trifluoromethylbenzyl group,a 4-benzyloxybenzyl group, a 2-nitrobenzyl group, a 3-nitrobenzyl group,a 4-nitrobenzyl group, a 2-cyanobenzyl group, a 3-cyanobenzyl group, a4-cyanobenzyl group, a 4-dimethylaminobenzyl group, a4-formylaminobenzyl group, a 2-acetylaminobenzyl group, a3-acetylaminobenzyl group, a 4-acetylaminobenzyl group, a4-benzoylaminobenzyl group, a 2-(2-fluorophenyl)ethyl group, a2-(3-fluorophenyl)ethyl group, a 2-(4-fluorophenyl)ethyl group, a2-(3,4-difluorophenyl)ethyl group, a 2-(2,4-difluorophenyl)ethyl group,a 2-(2-chlorophenyl)ethyl group, a 2-(3-chlorophenyl)ethyl group, a2-(4-chloro-phenyl)ethyl group, a 2-(2,4-dichlorophenyl)ethyl group, a2-(3,4-dichlorophenyl)ethyl group, a 2-(2-bromophenyl)ethyl group, a2-(3-bromophenyl)ethyl group, a 2-(4-bromophenyl)-ethyl group, a2-(2,4-dibromophenyl)ethyl group, a 2-(3,4-dibromophenyl)ethyl group, a2-(2-iodophenyl)ethyl group, a 2-(3-iodophenyl)ethyl group, a2-(4-iodophenyl)ethyl group, a 2-(2,3-diiodophenyl)ethyl group, a2-(3,4-diiodophenyl)ethyl group, a 2-(2-tolyl)ethyl group, a2-(3-tolyl)ethyl group, a 2-(4-tolyl)ethyl group, a2-(2-ethylphenyl)ethyl group, a 2-(3-ethylphenyl)ethyl group, a2-(4-ethylphenyl)ethyl group, a 2-(2-hydroxyphenyl)ethyl group, a2-(4-hydroxyphenyl)ethyl group, a 2-(2-methoxyphenyl)ethyl group, a2-(3-methoxyphenyl)ethyl group, a 2-(4-methoxyphenyl)ethyl group, a2-(2,4-dimethoxyphenyl)ethyl group, a 2-(3,4-dimethoxyphenyl)ethylgroup, a 2-(2-ethoxyphenyl)ethyl group, a 2-(4-ethoxyphenyl)ethyl group,a 2-(2-trifluoromethylphenyl)ethyl group, a2-(4-trifluoromethylphenyl)ethyl group, a 2-(4-benzyloxyphenyl)ethylgroup, a 2-(2-nitrophenyl)ethyl group, a 2-(3-nitrophenyl)ethyl group, a2-(4-nitrophenyl)ethyl group, a 2-(2-cyanophenyl)ethyl group, a2-(3-cyanophenyl)ethyl group, a 2-(4-cyanophenyl)ethyl group, a2-(4-dimethylaminophenyl)ethyl group, a 2-(4-formylaminophenyl)ethylgroup, a 2-(2-acetylaminophenyl)ethyl group, a2-(3-acetylaminophenyl)ethyl group, a 2-(4-acetylaminophenyl)ethylgroup, a 2-(4-benzoylaminophenyl)ethyl group, a 3-(2-fluorophenyl)propylgroup, a 3-(4-fluorophenyl)propyl group, a 3-(4-chlorophenyl)propylgroup, a 3-(4-bromophenyl)propyl group, a 3-(4-iodophenyl)propyl group,a 3-(2-chlorophenyl)propyl group, a 3-(2-methoxyphenyl)propyl group, a3-(4-methoxyphenyl)propyl group, a 3-(3,4-dimethoxyphenyl)propyl group,a 3-(4-trifluoromethylphenyl)propyl group, a3-(2-trifluoromethylphenyl)propyl group, a 3-(4-nitrophenyl)propylgroup, a 3-(4-cyanophenyl)propyl group, a 3-(4-acetylaminophenyl) propylgroup, and the like, preferably a 2-fluorobenzyl group, a 3-fluorobenzylgroup, a 4-fluorobenzyl group, a 2-chlorobenzyl group, a 3-chlorobenzylgroup, a 4-chlorobenzyl group, a 2-bromobenzyl group, a 3-bromobenzylgroup, a 4-bromobenzyl group, a 2-iodobenzyl group, a 3-iodobenzylgroup, a 4-iodobenzyl group, a 2-methylbenzyl group, a 3-methylbenzylgroup, a 4-methylbenzyl group, a 2-hydroxybenzyl group, a4-hydroxybenzyl group, a 2-methoxybenzyl group, a 3-methoxybenzyl group,a 4-methoxybenzyl group, a 3,4-dimethoxybenzyl group, a2-trifluoromethylbenzyl group, a 4-trifluoromethylbenzyl group, a4-benzyloxybenzyl group, a 2-nitrobenzyl group, a 3-nitrobenzyl group, a4-nitrobenzyl group, a 2-cyanobenzyl group, a 3-cyanobenzyl group, a4-cyanobenzyl group, a 4-formylaminobenzyl group, a 3-acetylaminobenzylgroup, a 4-acetylaminobenzyl group, a 4-benzoylaminobenzyl group, a2-(2-fluorophenyl)ethyl group, a 2-(3-fluorophenyl)ethyl group, a2-(4-fluorophenyl)ethyl group, a 2-(2-chlorophenyl)ethyl group, a2-(3-chlorophenyl)ethyl group, a 2-(4-chlorophenyl)ethyl group, a2-(2-bromophenyl)ethyl group, a 2-(3-bromophenyl)ethyl group, a2-(4-bromophenyl)ethyl group, a 2-(2-iodophenyl)ethyl group, a2-(3-iodophenyl)ethyl group, a 2-(4-iodophenyl)ethyl group, a2-(2-tolyl)ethyl group, a 2-(3-tolyl)ethyl group, a 2-(4-tolyl)ethylgroup, a 2-(2-ethylphenyl)ethyl group, a 2-(2-hydroxyphenyl)ethyl group,a 2-(4-hydroxyphenyl)ethyl group, a 2-(2-methoxyphenyl)ethyl group, a2-(3-methoxyphenyl)ethyl group, a 2-(4-methoxyphenyl)ethyl group, a2-(2,4-dimethoxyphenyl)ethyl group, a 2-(3,4-dimethoxyphenyl)ethylgroup, a 2-(2-trifluoromethylphenyl)ethyl group, a2-(4-trifluoromethylphenyl)ethyl group, a 2-(4-benzyloxyphenyl)ethylgroup, a 2-(2-nitrophenyl)ethyl group, a 2-(3-nitrophenyl)ethyl group, a2-(4-nitrophenyl)ethyl group, a 2-(2-cyanophenyl)ethyl group, a2-(3-cyanophenyl)ethyl group, a 2-(4-cyanophenyl)ethyl group, a2-(2-acetylaminophenyl)ethyl group, a 2-(3-acetylaminophenyl)ethylgroup, a 2-(4-acetylaminophenyl)ethyl group, a2-(4-benzoylaminophenyl)ethyl group, a 3-(2-fluorophenyl)propyl group, a3-(4-fluorophenyl)propyl group, a 3-(4-chlorophenyl)propyl group, a3-(4-bromophenyl)propyl group, a 3-(4-iodophenyl)propyl group, a3-(2-chlorophenyl)propyl group, a 3-(2-methoxyphenyl)propyl group, a3-(4-methoxyphenyl)propyl group, a 3-(3,4-dimethoxyphenyl)propyl group,a 3-(4-trifluoromethylphenyl)propyl group, a3-(2-trifluoromethylphenyl)propyl group, a 3-(4-nitrophenyl)propylgroup, a 3-(4-cyanophenyl)propyl group, a 3-(4-acetylaminophenyl)propylgroup, more preferably a 2-fluorobenzyl group, a 4-fluorobenzyl group, a2-chlorobenzyl group, a 4-chlorobenzyl group, a 2-bromobenzyl group, a4-bromobenzyl group, a 2-iodobenzyl group, a 4-iodobenzyl group, a2-methylbenzyl group, a 4-methylbenzyl group, a 4-hydroxybenzyl group, a2-methoxybenzyl group, a 4-methoxybenzyl group, a 3,4-dimethoxybenzylgroup, a 2-trifluoromethylbenzyl group, a 4-trifluoromethylbenzyl group,a 4-benzyloxybenzyl group, a 2-nitrobenzyl group, a 4-nitrobenzyl group,a 2-cyanobenzyl group, a 3-cyanobenzyl group, a 4-cyanobenzyl group, a3-acetylaminobenzyl group, a 4-acetylaminobenzyl group, a2-(2-fluorophenyl)ethyl group, a 2-(4-fluorophenyl)ethyl group, a2-(2-chlorophenyl)ethyl group, a 2-(4-chlorophenyl)ethyl group, a2-(2-bromophenyl)ethyl group, a 2-(4-bromophenyl)ethyl group, a2-(2-iodophenyl)ethyl group, a 2-(4-iodophenyl)ethyl group, a2-(2-tolyl)ethyl group, a 2-(4-tolyl)ethyl group, a2-(4-hydroxyphenyl)ethyl group, a 2-(2-methoxyphenyl)ethyl group, a2-(4-methoxyphenyl)ethyl group, a 2-(3,4-dimethoxyphenyl)ethyl group, a2-(2-trifluoromethylphenyl)ethyl group, a2-(4-trifluoromethylphenyl)ethyl group, a 2-(4-benzyloxyphenyl)ethylgroup, a 2-(2-nitrophenyl)ethyl group, a 2-(4-nitrophenyl)ethyl group, a2-(2-cyanophenyl)ethyl group, a 2-(4-cyanophenyl)ethyl group, a2-(2-acetylaminophenyl)ethyl group, a 2-(4-acetylaminophenyl)ethylgroup.

The substituted or unsubstituted aryl group of the above-mentioned R¹has the same meanings as that of the substituted or unsubstituted arylgroup of the above-mentioned Ar.

R² of Compound (I) is a hydrogen atom or R¹ and R² may bind to eachother to form a ring. When R² is a hydrogen atom, it becomes anN-substituted β-amino acid alkyl ester represented by the formula (I-a).Also, as the case where R¹ and R² bind to form a ring, there may bementioned a case where it forms a C₃ to C₆ saturated ring, and of these,the case where it forms a C₄ saturated ring is particularly preferred.When R¹ and R² bind to form a C₄ saturated ring, it becomes anN-substituted 2-homopipecolic acid ester represented by the formula(I-b).

R³ and R⁴ of the Compound (I) each independently represent a hydrogenatom, a substituted or unsubstituted alkyl group or a substituted orunsubstituted aryl group.

The above-mentioned substituted or unsubstituted alkyl group has thesame meanings as that of the substituted or unsubstituted alkyl group ofthe above-mentioned R¹, and the above-mentioned substituted orunsubstituted aryl group has the same meanings as that of thesubstituted or unsubstituted aryl group of the above-mentioned Ar.

R⁵ of Compound (I) represents a substituted or unsubstituted alkylgroup.

The substituted or unsubstituted alkyl group of the above-mentioned R⁵has the same meanings as that of the substituted or unsubstituted alkylgroup of the above-mentioned R¹.

Compound (I-a) to be used in the hydrolysis reaction of the presentinvention can be easily synthesized by, for example, subjecting β-ketoesters and 1-arylalkylamines to dehydration condensation to formcorresponding enamines, and then subjecting the resulting compound toreduction by hydrogen (for example, Current Medicinal Chemistry, 6, 955(1999)). Also, Compound (I-b) to be used in the hydrolysis reaction ofthe present invention can be easily synthesized by, for example,oxidizing 2-(2-piperidin)ethanol to synthesize 2-carboxymethylpiperidine(Can. J. Chem., 53, 41 (1975)), then, esterifying the resulting compoundto make 2-carbomethoxymethylpiperidine (Can. J. Chem., 65, 2722 (1987)),and further subjecting to benzylation of the resulting compound(described in Reference example 3 mentioned below).

Specific examples of Compound (I-a) having the above-mentioned Ar, R¹,R³, R⁴ and R⁵ may include, for example,

-   methyl 3-benzylaminobutyrate,-   ethyl 3-benzylaminobutyrate,-   n-propyl 3-benzylaminobutyrate,-   b-butyl 3-benzylaminobutyrate,-   n-octyl 3-benzylaminobutyrate,-   2-chloroethyl 3-benzylaminobutyrate,-   2,2,2-trichloroethyl 3-benzylaminobutyrate,-   2,2,2-trifluoroethyl 3-benzylaminobutyrate,-   2-cyanoethyl 3-benzylaminobutyrate,-   methyl 3-(4-chlorobenzylamino)butyrate,-   methyl 3-(4-fluorobenzylamino)butyrate,-   methyl 3-(4-methoxybenzylamino)acetate,-   methyl 3-(4-hydroxybenzyl)aminoacetate,-   methyl 3-(4-methylbenzyl)aminobutyrate,-   methyl 3-(3,4-dimethoxybenzyl)aminobutyrate,-   methyl 3-(3,4-methylenedioxybenzyl)aminobutyrate,-   methyl 3-(4-nitrobenzyl)aminobutyrate,-   methyl 3-(1-naphthylmethyl)aminobutyrate,-   methyl 3-(1-phenylethyl)aminobutyrate,-   methyl 3-(1-(2-chlorophenyl)ethyl)aminobutyrate,-   methyl 3-(1-(1-naphthyl)ethyl)aminobutyrate,-   methyl 3-diphenylmethylaminobutyrate,-   methyl 3-tritylaminobutyrate,-   methyl 3-benzylaminopentanoate,-   ethyl 3-benzylaminopentanoate,-   2,2,2-trifluoroethyl 3-benzylamino pentanoate,-   methyl 3-(4-chlorobenzylamino) pentanoate,-   methyl 3-(4-methoxybenzylamino)pentanoate,-   ethyl 3-(4-nitrobenzylamino)pentanoate,-   methyl 3-benzylaminohexanoate,-   ethyl 3-benzylaminohexanoate,-   2,2,2-trichloroethyl 3-benzylaminohexanoate,-   2,2,2-trifluoroethyl 3-benzylaminohexanoate,-   methyl 3-benzylamino-4-methylpentanoate,-   ethyl 3-benzylamino-4-methylpentanoate,-   n-propyl 3-benzylamino-4-methylpentanoate,-   n-butyl 3-benzylamino-4-methylpentanoate,-   n-pentyl 3-benzylamino-4-methylpentanoate,-   n-octyl 3-benzylamino-4-methylpentanoate,-   2-chloroethyl 3-benzylamino-4-methylpentanoate,-   2,2,2-trichloroethyl 3-benzylamino-4-methylpentanoate,-   2,2,2-trifluoroethyl 3-benzylamino-4-methylpentanoate,-   methyl 3-(2-methylbenzyl)-4-methylpentanoate,-   methyl 3-(3-methylbenzyl)-4-methylpentanoate,-   methyl 3-(4-methylbenzyl)-4-methylpentanoate,-   methyl 3-(2-methoxybenzyl)-4-methylpentanoate,-   methyl 3-(3-methoxybenzyl)amino-4-methylpentanoate,-   methyl 3-(4-methoxybenzyl)amino-4-methylpentanoate,-   butyl 3-(2-chlorobenzyl)amino-4-methylpentanoate,-   ethyl 3-(3-chlorobenzyl)amino-4-methylpentanoate,-   methyl 3-(4-chlorobenzyl)amino-4-methylpentanoate,-   methyl 3-(2-bromobenzyl)amino-4-methylpentanoate,-   methyl 3-(3-bromobenzyl)amino-4-methylpentanoate,-   ethyl 3-(4-bromobenzyl)amino-4-methylpentanoate,-   methyl 3-(2-fluorobenzyl)amino-4-methylpentanoate,-   methyl 3-(2-nitrobenzyl)amino-4-methylpentanoate,-   methyl 3-(4-nitrobenzyl)amino-4-methylpentanoate,-   methyl 3-(2-methoxybenzyl)amino-4-methylpentanoate,-   methyl 3-(3-methoxybenzyl)amino-4-methylpentanoate,-   methyl 3-(4-methoxybenzyl)amino-4-methylpentanoate,-   methyl 3-(3,4-dimethoxybenzyl)amino-4-methylpentanoate,-   methyl 3-(3,4-methylenedioxybenzyl)amino-4-methylpentanoate,-   methyl 3-benzylamino-4-chlorobutyrate,-   ethyl 3-benzylamino-4-chlorobutyrate,-   methyl 3-benzylamino-4-hydroxybutyrate,-   ethyl 3-benzylamino-4-hydroxybutyrate,-   methyl 3-benzylamino-3-phenylpropionate,-   ethyl 3-benzylamino-3-phenylpropionate,-   n-propyl 3-benzylamino-3-phenylpropionate,-   n-butyl 3-benzylamino-3-phenylpropionate,-   n-octyl 3-benzylamino-3-phenylpropionate,-   2-chloroethyl 3-benzylamino-3-phenylpropionate,-   2,2,2-trichloroethyl 3-benzylamino-3-phenylpropionate,-   2,2,2-trifluoroethyl 3-benzylamino-3-phenylpropionate,-   2-cyanoethyl 3-benzylamino-3-phenylpropionate,-   methyl 3-(4-methoxybenzylamino)-3-phenylpropionate,-   methyl 3-(4-hydroxybenzyl)amino-3-phenylpropionate,-   methyl 3-(4-methylbenzyl)amino-3-phenylpropionate,-   methyl 3-(3,4-dimethoxybenzyl)amino-3-phenylpropionate,-   methyl 3-(3,4-methylenedioxybenzyl)amino-3-phenylpropionate,-   methyl 3-(4-nitrobenzyl)amino-3-phenylpropionate,-   methyl 3-(1-phenylethyl)amino-3-phenylpropionate,-   methyl 3-(1-(1-naphthyl)ethyl)amino-3-phenylpropionate,-   methyl 3-diphenylmethylamino-3-phenylpropionate,-   methyl 3-tritylamino-3-phenylpropionate,-   methyl 3-benzylamino-3-(2-fluorophenyl)propionate,-   methyl 3-benzylamino-3-(4-fluorophenyl)propionate,-   ethyl 3-benzylamino-3-(4-fluorophenyl)propionate,-   methyl 3-diphenylmethylamino-3-(4-fluorophenyl)propionate,-   methyl 3-benzylamino-3-(2-chlorophenyl)phenylpropionate,-   methyl 3-benzylamino-3-(4-chlorophenyl)phenylpropionate,-   methyl 3-benzylamino-3-(4-bromophenyl)propionate,-   ethyl 3-benzylamino-3-(4-iodophenyl)propionate,-   methyl 3-benzylamino-3-(4-hydroxyphenyl)propionate,-   ethyl 3-benzylamino-3-(2-hydroxyphenyl)propionate,-   methyl 3-benzylamino-3-(2-methoxyphenyl)propionate,-   methyl 3-benzylamino-3-(4-methoxyphenyl)propionate,-   ethyl 3-benzylamino-3-(4-methoxyphenyl)propionate,-   methyl 3-diphenylmethylamino-3-(4-methoxyphenyl)propionate,-   methyl 3-benzylamino-3-(3,4-dimethoxyphenyl)propionate,-   ethyl 3-benzylamino-3-(3,4-dimethoxyphenyl)propionate,-   methyl 3-diphenylmethylamino-3-(3,4-dimethoxyphenyl)propionate,-   methyl 3-benzylamino-3-(3,4-methylenedioxyphenyl)propionate,-   ethyl 3-benzylamino-3-(3,4-methylenedioxyphenyl)propionate,-   ethyl 3-diphenylmethylamino-3-(3,4-methylenedioxyphenyl)propionate,-   methyl 3-benzylamino-3-(4-tolyl)propionate,-   ethyl 3-benzylamino-3-(4-tolyl)propionate,-   methyl 3-diphenylmethylamino-3-(4-tolyl)propionate,-   methyl 3-benzylamino-3-(2-tolyl)propionate,-   methyl 3-benzylamino-4-phenylbutyrate,-   ethyl 3-benzylamino-4-phenylbutyrate,-   methyl 3-benzylamino-4-(4-fluorophenyl)butyrate,-   methyl 3-benzylamino-4-(2-fluorophenyl)butyrate,-   methyl 3-benzylamino-4-(4-chlorophenyl)butyrate,-   methyl 3-benzylamino-4-(4-iodophenyl)butyrate,-   methyl 3-benzylamino-4-(4-methoxyphenyl)butyrate,-   methyl 3-benzylamino-4-(2-methoxyphenyl)butyrate,-   methyl 3-benzylamino-4-(3,4-dimethoxyphenyl)butyrate,-   methyl 3-benzylamino-4-(4-hydroxyphenyl)butyrate,-   methyl 3-benzylamino-5-phenylpentanoate,-   methyl 3-benzylamino-5-(4-fluorophenyl)pentanoate,-   methyl 3-benzylamino-5-(4-chlorophenyl)pentanoate,-   methyl 3-benzylamino-5-(2-fluorophenyl)pentanoate,-   methyl 3-benzylamino-5-(4-methoxyphenyl)pentanoate,-   methyl 3-benzylamino-5-(2-methoxyphenyl)pentanoate,-   methyl 3-benzylamino-5-(3,4-dimethoxyphenyl)pentanoate,-   methyl 3-(1-phenylethyl)amino-5-phenylpentanoate,-   methyl 3-benzhydrylamino-5-phenylpentanoate,-   methyl 3-(1-phenylethyl)amino-4-chlorobutyrate,-   ethyl 3-benzhydrylamino-4-hydroxybutyrate,-   ethyl 3-(1-phenylethyl)amino-4-hydroxybutyrate,-   ethyl 3-benzhydrylamino-4-hydroxybutyrate,-   methyl 3-(1-phenylethyl)aminobutyrate,-   methyl 3-benzhydrylaminopentanoate,-   methyl 3-(1-phenylethyl)amino-4-methylpentanoate,-   ethyl 3-benzhydrylamino-4-methylpentanoate,-   methyl 3-(1-naphthylmethyl)aminobutyrate,-   methyl 3-(2-naphthylmethyl)aminobutyrate,-   methyl 3-(2-naphthylmethyl)aminopentanoate,-   methyl 3-(2-naphthylmethyl)amino-4-methylpentanoate,-   methyl 3-(1-(1-naphthyl)ethylamino-4-methylpentanoate,    etc., preferably-   methyl 3-benzylaminobutyrate,-   ethyl 3-benzylaminobutyrate,-   n-octyl 3-benzylaminobutyrate,-   2-chloroethyl 3-benzylaminobutyrate,-   2,2,2-trichloroethyl 3-benzylaminobutyrate,-   2,2,2-trifluoroethyl 3-benzylaminobutyrate,-   methyl 3-(4-chlorobenzylamino)butyrate,-   methyl 3-(4-fluorobenzylamino)butyrate,-   methyl 3-(4-methoxybenzylamino)acetate,-   methyl 3-(4-hydroxybenzyl)aminoacetate,-   methyl 3-(4-methylbenzyl)aminobutyrate,-   methyl 3-(3,4-dimethoxybenzyl)aminobutyrate,-   methyl 3-(3,4-methylenedioxybenzyl)aminobutyrate,-   methyl 3-(4-nitrobenzyl)aminobutyrate,-   methyl 3-(1-naphthylmethyl)aminobutyrate,-   methyl 3-(1-phenylethyl)aminobutyrate,-   methyl 3-(1-(1-naphthyl)ethyl)aminobutyrate,-   methyl 3-diphenylmethylaminobutyrate,-   methyl 3-benzylaminopentanoate,-   ethyl 3-benzylaminopentanoate,-   methyl 3-(4-chlorobenzylamino)pentanoate,-   methyl 3-(4-methoxybenzylamino)pentanoate,-   ethyl 3-(4-nitrobenzylamino)pentanoate,-   methyl 3-benzylaminohexanoate,-   ethyl 3-benzylaminohexanoate,-   2,2,2-trifluoroethyl 3-benzylaminohexanoate,-   methyl 3-benzylamino-4-methylpentanoate,-   ethyl 3-benzylamino-4-methylpentanoate,-   n-octyl 3-benzylamino-4-methylpentanoate,-   2-chloroethyl 3-benzylamino-4-methylpentanoate,-   2,2,2-trichloroethyl 3-benzylamino-4-methylpentanoate,-   2,2,2-trifluoroethyl 3-benzylamino-4-methylpentanoate,-   methyl 3-(2-methylbenzyl)-4-methylpentanoate,-   methyl 3-(4-methylbenzyl)-4-methylpentanoate,-   methyl 3-(2-methoxybenzyl)-4-methylpentanoate,-   methyl 3-(4-methoxybenzyl)amino-4-methylpentanoate,-   butyl 3-(2-chlorobenzyl)amino-4-methylpentanoate,-   methyl 3-(4-chlorobenzyl)amino-4-methylpentanoate,-   methyl 3-(4-nitrobenzyl)amino-4-methylpentanoate,-   methyl 3-(2-methoxybenzyl)amino-4-methylpentanoate,-   methyl 3-(4-methoxybenzyl)amino-4-methylpentanoate,-   methyl 3-(3,4-dimethoxybenzyl)amino-4-methylpentanoate,-   methyl 3-(3,4-methylenedioxybenzyl)amino-4-methylpentanoate,-   methyl 3-benzylamino-4-chlorobutyrate,-   ethyl 3-benzylamino-4-chlorobutyrate,-   methyl 3-benzylamino-4-hydroxybutyrate,-   methyl 3-benzylamino-3-phenylpropionate,-   ethyl 3-benzylamino-3-phenylpropionate,-   2-chloroethyl 3-benzylamino-3-phenylpropionate,-   2,2,2-trichloroethyl 3-benzylamino-3-phenylpropionate,-   2,2,2-trifluoroethyl 3-benzylamino-3-phenylpropionate,-   2-cyanoethyl 3-benzylamino-3-phenylpropionate,-   methyl 3-(4-methoxybenzylamino)-3-phenylpropionate,-   methyl 3-(4-hydroxybenzyl)amino-3-phenylpropionate,-   methyl 3-(3,4-dimethoxybenzyl)amino-3-phenylpropionate,-   methyl 3-(3,4-methylenedioxybenzyl)amino-3-phenylpropionate,-   methyl 3-(1-phenylethyl)amino-3-phenylpropionate,-   methyl 3-(1-(1-naphthyl)ethyl)amino-3-phenylpropionate,-   methyl 3-diphenylmethylamino-3-phenylpropionate,-   methyl 3-tritylamino-3-phenylpropionate,-   methyl 3-benzylamino-3-(2-fluorophenyl)propionate,-   methyl 3-benzylamino-3-(4-fluorophenyl)propionate,-   ethyl 3-benzylamino-3-(4-fluorophenyl)propionate,-   methyl 3-diphenylmethylamino-3-(4-fluorophenyl)propionate,-   methyl 3-benzylamino-3-(2-chlorophenyl)phenylpropionate,-   methyl 3-benzylamino-3-(4-chlorophenyl)phenylpropionate,-   methyl 3-benzylamino-3-(4-hydroxyphenyl)propionate,-   ethyl 3-benzylamino-3-(2-hydroxyphenyl)propionate,-   methyl 3-benzylamino-3-(2-methoxyphenyl)propionate,-   methyl 3-benzylamino-3-(4-methoxyphenyl)propionate,-   ethyl 3-benzylamino-3-(4-methoxyphenyl)propionate,-   methyl 3-diphenylmethylamino-3-(4-methoxyphenyl)propionate,-   methyl 3-benzylamino-3-(3,4-dimethoxyphenyl)propionate,-   ethyl 3-benzylamino-3-(3,4-dimethoxyphenyl)propionate,-   methyl 3-diphenylmethylamino-3-(3,4-dimethoxyphenyl)propionate,-   methyl 3-benzylamino-3-(3,4-methylenedioxyphenyl)propionate,-   ethyl 3-benzylamino-3-(3,4-methylenedioxyphenyl)propionate,-   ethyl 3-diphenylmethylamino-3-(3,4-methylenedioxyphenyl)propionate,-   methyl 3-benzylamino-3-(4-tolyl)propionate,-   ethyl 3-benzylamino-3-(4-tolyl)propionate,-   methyl 3-diphenylmethylamino-3-(4-tolyl)propionate,-   methyl 3-benzylamino-3-(2-tolyl)propionate,-   methyl 3-benzylamino-4-phenylbutyrate,-   methyl 3-benzylamino-4-(4-fluorophenyl)butyrate,-   methyl 3-benzylamino-4-(2-fluorophenyl)butyrate,-   methyl 3-benzylamino-4-(4-chlorophenyl)butyrate,-   methyl 3-benzylamino-4-(4-methoxyphenyl)butyrate,-   methyl 3-benzylamino-4-(2-methoxyphenyl)butyrate,-   methyl 3-benzylamino-4-(3,4-dimethoxyphenyl)butyrate,-   methyl 3-benzylamino-4-(4-hydroxyphenyl)butyrate,-   methyl 3-benzylamino-5-phenylpentanoate,-   methyl 3-benzylamino-5-(4-fluorophenyl)pentanoate,-   methyl 3-benzylamino-5-(4-chlorophenyl)pentanoate,-   methyl 3-benzylamino-5-(2-fluorophenyl)pentanoate,-   methyl 3-benzylamino-5-(4-methoxyphenyl)pentanoate,-   methyl 3-benzylamino-5-(2-methoxyphenyl)pentanoate,-   methyl 3-benzylamino-5-(3,4-dimethoxyphenyl)pentanoate,-   methyl 3-benzhydrylamino-5-phenylpentanoate,-   methyl 3-(1-phenylethyl)amino-4-chlorobutyrate,-   ethyl 3-benzhydrylamino-4-hydroxybutyrate,-   methyl 3-benzhydrylaminopentanoate,-   methyl 3-(1-phenylethyl)amino-4-methylpentanoate,-   ethyl 3-benzhydrylamino-4-methylpentanoate,    more preferably-   methyl 3-benzylaminobutyrate,-   ethyl 3-benzylaminobutyrate,-   methyl 3-benzylamino-3-phenylpropionate-   ethyl 3-benzylamino-3-phenylpropionate-   methyl 3-benzylamino-3-(4-tolyl)propionate,-   ethyl 3-benzylamino-3-(4-tolyl)propionate,-   methyl 3-benzylamino-3-(4-fluorophenyl)propionate-   methyl 3-benzylamino-3-(3,4-methylenedioxyphenyl)propionate,-   ethyl 3-benzylamino-3-(3,4-methylenedioxyphenyl)propionate,-   methyl 3-benzylaminopentanoate,-   ethyl 3-benzylaminopentanoate,-   methyl 3-benzylaminohexanoate,-   ethyl 3-benzylaminohexanoate,-   methyl 3-benzylamino-4-methylpentanoate, and-   ethyl 3-benzylamino-4-methylpentanoate.

Also, specific examples of Compound (1-b) having the above-mentioned Ar,R³, R⁴ and R⁵ may include, for example,

-   methyl 1-benzyl-2-homopipecolate,-   ethyl 1-benzyl-2-homopipecolate,-   n-butyl 1-benzyl-2-homopipecolate,-   n-octyl 1-benzyl-2-homopipecolate,-   2-chloroethyl 1-benzyl-2-homopipecolate,-   2,2,2-trichloroethyl 1-benzyl-2-homopipecolate,-   2,2,2-trifluoroethyl 1-benzyl-2-homopipecolate,-   2-cyanoethyl 1-benzyl-2-homopipecolate,-   methyl 1-(4-methylbenzyl)-2-homopipecolate,-   ethyl 1-(hydroxybenzyl)-2-homopipecolate,-   methyl 1-(3,4-dihydroxybenzyl)-2-homopipecolate,-   methyl 1-(4-chlorobenzyl)-2-homopipecolate,-   ethyl 1-(4-fluorobenzyl)-2-homopipecolate,-   methyl 1-(4-methoxybenzyl)-2-homopipecolate,-   methyl 1-(3,4-dimethoxybenzyl)-2-homopipecolate,-   methyl 1-(3,4-methylenedioxybenzyl)-2-homopipecolate,-   methyl 1-(4-nitrobenzyl)-2-homopipecolate,-   methyl 1-(1-naphthylmethyl)-2-homopipecolate,-   methyl 1-(2-naphthylmethyl)-2-homopipecolate,-   methyl 1-(1-phenylethyl)-2-homopipecolate,-   methyl 1-(1-(2-chlorophenyl)ethyl)-2-homopipecolate,-   methyl 1-(1-(1-naphthyl)ethyl)-2-homopipecolate,-   methyl 1-diphenylmethyl-2-homopipecolate,-   2,2,2-trifluoroethyl 1-trityl-2-homopipecolate,-   methyl 1-di(4-methoxyphenyl)methyl-2-homopipecolate, etc.,    preferably-   methyl 1-benzyl-2-homopipecolate,-   ethyl 1-benzyl-2-homopipecolate,-   n-octyl 1-benzyl-2-homopipecolate,-   2-chloroethyl 1-benzyl-2-homopipecolate,-   2,2,2-trichloroethyl 1-benzyl-2-homopipecolate,-   2,2,2-trifluoroethyl 1-benzyl-2-homopipecolate,-   methyl 1-(4-methylbenzyl)-2-homopipecolate,-   ethyl 1-(hydroxybenzyl)-2-homopipecolate,-   methyl 1-(4-chlorobenzyl)-2-homopipecolate,-   methyl 1-(4-methoxybenzyl)-2-homopipecolate,-   methyl 1-(4-nitrobenzyl)-2-homopipecolate,-   methyl 1-(1-naphthylmethyl)-2-homopipecolate,-   methyl 1-(1-phenylethyl)-2-homopipecolate,-   methyl 1-(1-(1-naphthyl)ethyl)-2-homopipecolate,-   methyl 1-diphenylmethyl-2-homopipecolate,    more preferably-   methyl 1-benzyl-2-homopipecolate,-   ethyl 1-benzyl-2-homopipecolate,-   methyl 1-(4-methoxybenzyl)-2-homopipecolate,-   methyl 1-(1-phenylethyl)-2-homopipecolate,-   methyl 1-diphenylmethyl-2-homopipecolate.

As the hydrolase to be used in the hydrolysis of the present invention,there may be mentioned, for example, protease, esterase, lipase and thelike, preferably a lipase of microorganisms which are capable ofisolating from yeast or bacteria, more preferably a lipase originatedfrom Pseudomonas (for example, Amano PS (available from AmanoenzymeCo.), etc.), a lipase originated from Candida antarctica (for example,Chirazyme L-2 (available from Roche AG), etc.), particularly preferablya lipase originated from Candida antarctica is used. Incidentally, thesehydrolases may be used in a natural form or a commercially availableproduct as such as a fixed enzyme, and may be used alone or incombination of two or more kinds.

An amount of the above-mentioned hydrolase to be used is preferably 0.1to 1000 mg, more preferably 1 to 200 mg based on 1 g of Compound (I).

The hydrolysis reaction of the present invention is preferably carriedout in an aqueous solution, in a buffer solvent, in a 2-phase solvent ofan organic solvent and water, or in a 2-phase solvent of an organicsolvent and a buffer.

As the above-mentioned water, purified water such as deionized water,distilled water, etc., is preferably used. Incidentally, when water isused as the solvent, a weak base such as potassium hydrogen carbonate orsodium hydrogen carbonate may be present in the reaction system toneutralize the formed Compound (II). An amount of the above-mentionedweak base to be used is preferably 0.5 to 1.0 mol based on 1 mol ofCompound (II).

As the above-mentioned buffer solution, there may be mentioned, forexample, an aqueous solution of an inorganic acid salt such as anaqueous sodium phosphate solution, an aqueous potassium phosphatesolution, etc.; an aqueous solution of an organic acid salt such as anaqueous sodium acetate solution, an aqueous sodium citrate solution,etc., preferably an aqueous solution of an inorganic acid salt, morepreferably aqueous sodium phosphate solution is used. These aqueoussolutions may be used alone or in admixture of two kinds or more.

A concentration of the buffer solution is preferably 0.01 to 2 mol/l,more preferably 0.05 to 0.5 mol/l, and a pH of the buffer solution ispreferably 4 to 9, more preferably 6 to 8.

As the above-mentioned organic solvent, there may be mentioned, forexample, an aliphatic hydrocarbon such as n-pentane, n-hexane,n-heptane, n-octane, cyclopentane, cyclohexane, cyclopentane, etc.; anaromatic hydrocarbon such as benzene, toluene, xylene, etc.; an ethersuch as diethyl ether, t-butyl methyl ether, diisopropyl ether,tetrahydrofuran, 1,4-dioxane, etc., preferably n-hexane, n-heptane,cyclopentane, cyclohexane, toluene, diisopropyl ether, t-butyl methylether, tetrahydrofuran, more preferably n-hexane, cyclohexane,diisopropyl ether, t-butyl methyl ether and/or tetrahydrofuran is/areused.

An amount of the solvent to be used (water solvent, a buffer solutionsolvent, a 2-phase solvent of an organic solvent and water, or a 2-phasesolvent of an organic solvent and a buffer solution) in the hydrolysisreaction of the present invention is preferably 2 to 200 ml, morepreferably 5 to 80 ml based on 1 g of Compound (I).

In the hydrolysis reaction of the present invention, an amount of theorganic solvent to be used when the 2-phase solvent of an organicsolvent and water or the 2-phase solvent of an organic solvent and abuffer solution is used is preferably 0.1 to 10 ml, more preferably 0.5to 5 ml based on 1 ml of water or the buffer solution.

The hydrolysis reaction of the present invention can be carried out, forexample, by mixing Compound (I), a hydrolase and a solvent (watersolvent, a buffer solvent, a 2-phase solvent of an organic solvent andwater, or a 2-phase solvent of an organic solvent and a buffersolution), and reacting the mixture under stirring, and the like. Thereaction temperature at that time is preferably 0 to 80° C., morepreferably 10 to 50° C., and the reaction pressure is not specificallylimited.

Compound (II) and Compound (III) obtained by the hydrolysis reaction ofthe present invention can be obtained by, for example, after completionof the reaction, removing insoluble materials by filtrating the reactionmixture, extracting the obtained filtrate with an organic solvent, andconcentrating the extract to obtain the product as a mixture of Compound(II) and Compound (III). Incidentally, they can be isolated respectivelyfrom the above-mentioned mixture by a general purifying method such ascrystallization, recrystallization, distillation, column chromatography,etc., by preferably column chromatography, more preferably isolated bysilica gel column chromatography.

Specific examples of Compound (II-a) obtained by the hydrolysis reactionof the present invention may include, for example,

-   optically active (R or S)-3-benzylaminobutyric acid,-   optically active (R or S)-3-(4-chlorobenzylamino)butyric acid,-   optically active (R or S)-3-(4-fluorobenzylamino)butyric acid,-   optically active (R or S)-3-(4-methoxybenzylamino)acetic acid,-   optically active (R or S)-3-(4-hydroxybenzyl)aminoacetic acid,-   optically active (R or S)-3-(4-methylbenzyl)aminobutyric acid,-   optically active (R or S)-3-(3,4-dimethoxybenzyl)aminobutyric acid,-   optically active (R or S)-3-(3,4-methylenedioxybenzyl)aminobutyric    acid,-   optically active (R or S)-3-(4-nitrobenzyl)aminobutyric acid,-   optically active (R or S)-3-(1-naphthylmethyl)aminobutyric acid,-   optically active (R or S)-3-(1-phenylethyl)aminobutyric acid,-   optically active (R or S)-3-(1-(2-chlorophenyl)ethyl)aminobutyric    acid,-   optically active (R or S)-3-(1-(1-naphthyl)ethyl)aminobutyric acid,-   optically active (R or S)-3-diphenylmethylaminobutyric acid,-   optically active (R or S)-3-tritylaminobutyric acid,-   optically active (R or S)-3-benzylaminopentanoic acid,-   optically active (R or S)-3-(4-chlorobenzylamino)pentanoic acid,-   optically active (R or S)-3-(4-methoxybenzyl)aminopentanoic acid,-   optically active (R or S)-3-(4-nitrobenzyl)aminopentanoic acid,-   optically active (R or S)-3-benzylaminohexanoic acid,-   optically active methyl (R or S)-3-benzylamino-4-methylpentanoate,-   optically active (R or S)-3-(2-methylbenzyl)-4-methylpentanoic acid,-   optically active (R or S)-3-(3-methylbenzyl)-4-methylpentanoic acid,-   optically active (R or S)-3-(4-methylbenzyl)-4-methylpentanoic acid,-   optically active (R or S)-3-(2-methoxybenzyl)amino-4-methylpentanoic    acid,-   optically active (R or S)-3-(3-methoxybenzyl)amino-4-methylpentanoic    acid,-   optically active (R or S)-3-(4-methoxybenzyl)amino-4-methylpentanoic    acid,-   optically active (R or S)-3-(2-chlorobenzyl)amino-4-methylpentanoic    acid,-   optically active (R or S)-3-(3-chlorobenzyl)amino-4-methylpentanoic    acid,-   optically active (R or S)-3-(4-chlorobenzyl)amino-4-methylpentanoic    acid,-   optically active (R or S)-3-(2-bromobenzyl)amino-4-methylpentanoic    acid,-   optically active (R or S)-3-(3-bromobenzyl)amino-4-methylpentanoic    acid,-   optically active (R or S)-3-(4-bromobenzyl)amino-4-methylpentanoic    acid,-   optically active (R or S)-3-(2-fluorobenzyl)amino-4-methylpentanoic    acid,-   optically active (R or S)-3-(2-nitrobenzyl)amino-4-methylpentanoic    acid,-   optically active (R or S)-3-(4-nitrobenzyl)amino-4-methylpentanoic    acid,-   optically active (R or S)-3-(2-methoxybenzyl)amino-4-methylpentanoic    acid,-   optically active (R or    S)-3-(3,4-dimethoxybenzyl)amino-4-methylpentanoic acid,-   optically active (R or    S)-3-(3,4-methylenedioxybenzyl)amino-4-methylpentanoic acid,-   optically active (R or S)-3-benzylamino-4-chlorobutyric acid,-   optically active (R or S)-3-benzylamino-4-hydroxybutyric acid,-   optically active (R or S)-3-benzylamino-3-phenylpropionic acid-   optically active (R or S)-3-(4-methoxybenzylamino)-3-phenylpropionic    acid,-   optically active (R or S)-3-(4-hydroxybenzyl)amino-3-phenylpropionic    acid,-   optically active (R or S)-3-(4-methylbenzyl)amino-3-phenylpropionic    acid,-   optically active (R or    S)-3-(3,4-dimethoxybenzyl)amino-3-phenylpropionic acid,-   optically active (R or    S)-3-(3,4-methylenedioxybenzyl)amino-3-phenylpropionic acid,-   optically active (R or S)-3-(4-nitrobenzyl)amino-3-phenylpropionic    acid,-   optically active (R or S)-3-(1-phenylethyl)amino-3-phenylpropionic    acid,-   optically active (R or    S)-3-(1-(1-naphthyl)ethyl)amino-3-phenylpropionic acid,-   optically active (R or S)-3-diphenylmethylamino-3-phenylpropionic    acid,-   optically active (R or S)-3-tritylamino-3-phenylpropionic acid,-   optically active (R or S)-3-benzylamino-3-(2-fluorophenyl)propionic    acid,-   optically active (R or S)-3-benzylamino-3-(4-fluorophenyl)propionic    acid,-   optically active (R or    S)-3-diphenylmethylamino-3-(4-fluorophenyl)propionic acid,-   optically active (R or    S)-3-benzylamino-3-(2-chlorophenyl)phenylpropionic acid,-   optically active (R or    S)-3-benzylamino-3-(4-chlorophenyl)phenylpropionic acid,-   optically active (R or S)-3-benzylamino-3-(4-bromophenyl)propionic    acid,-   optically active (R or S)-3-benzylamino-3-(4-iodophenyl)propionic    acid,-   optically active methyl (R or    S)-3-benzylamino-3-(4-hydroxyphenyl)propionate,-   optically active (R or S)-3-benzylamino-3-(2-hydroxyphenyl)propionic    acid,-   optically active (R or S)-3-benzylamino-3-(2-methoxyphenyl)propionic    acid,-   optically active (R or S)-3-benzylamino-3-(4-methoxyphenyl)propionic    acid,-   optically active (R or    S)-3-diphenylmethylamino-3-(4-methoxyphenyl)propionic acid,-   optically active (R or    S)-3-benzylamino-3-(3,4-dimethoxyphenyl)propionic acid,-   optically active (R or    S)-3-diphenylmethylamino-3-(3,4-dimethoxyphenyl)propionic acid,-   optically active (R or    S)-3-benzylamino-3-(3,4-methylenedioxyphenyl)propionic acid,-   3-diphenylmethylamino-3-(3,4-methylenedioxyphenyl)propionic acid,-   optically active (R or S)-3-benzylamino-3-(4-tolyl)propionic acid,-   optically active (R or S)-3-diphenylmethylamino-3-(4-tolyl)propionic    acid,-   optically active (R or S)-3-benzylamino-3-(2-tolyl)propionic acid,-   optically active (R or S)-3-benzylamino-4-phenylbutyric acid,-   optically active (R or S)-3-benzylamino-4-(4-fluorophenyl)butyric    acid,-   optically active (R or S)-3-benzylamino-4-(2-fluorophenyl)butyric    acid,-   optically active (R or S)-3-benzylamino-4-(4-chlorophenyl)butyric    acid,-   optically active (R or S)-3-benzylamino-4-(4-iodophenyl)butyric    acid,-   optically active (R or S)-3-benzylamino-4-(4-methoxyphenyl)butyric    acid,-   optically active (R or S)-3-benzylamino-4-(2-methoxyphenyl)butyric    acid,-   optically active (R or    S)-3-benzylamino-4-(3,4-dimethoxyphenyl)butyric acid,-   optically active (R or S)-3-benzylamino-4-(4-hydroxyphenyl)butyric    acid,-   optically active (R or S)-3-benzylamino-5-phenylpentanoic acid,-   optically active (R or S)-3-benzylamino-5-(4-fluorophenyl)pentanoic    acid,-   optically active (R or S)-3-benzylamino-5-(4-chlorophenyl)pentanoic    acid,-   optically active (R or S)-3-benzylamino-5-(2-fluorophenyl)pentanoic    acid,-   optically active (R or S)-3-benzylamino-5-(4-methoxyphenyl)pentanoic    acid,-   optically active (R or S)-3-benzylamino-5-(2-methoxyphenyl)pentanoic    acid,-   optically active (R or    S)-3-benzylamino-5-(3,4-dimethoxyphenyl)pentanoic acid,-   optically active (R or S)-3-(1-phenylethyl)amino-5-phenylpentanoic    acid,-   optically active (R or S)-3-benzhydrylamino-5-phenylpentanoic acid,-   optically active (R or S)-3-(1-phenylethyl)amino-4-chlorobutyric    acid,-   optically active (R or S)-3-benzhydrylamino-4-hydroxybutyric acid,-   optically active (R or S)-3-(1-phenylethyl)amino-4-hydroxybutyric    acid,-   optically active (R or S)-3-benzhydrylamino-4-hydroxybutyric acid,-   optically active (R or S)-3-benzhydrylaminopentanoic acid,-   optically active (R or S)-3-(1-phenylethyl)amino-4-methylpentanoic    acid,-   optically active (R or S)-3-benzhydrylamino-4-methylpentanoic acid,-   optically active (R or S)-3-(1-naphthylmethyl)aminobutyric acid,-   optically active (R or S)-3-(2-naphthylmethyl)aminobutyric acid,-   optically active (R or S)-3-(2-naphthylmethyl)aminopentanoic acid,-   optically active (R or    S)-3-(2-naphthylmethyl)amino-4-methylpentanoic acid,-   optically active (R or    S)-3-(1-(1-naphthyl)ethyl)amino-4-methylpentanoic acid,    and the like, preferably-   optically active (R or S)-3-benzylaminobutyric acid,-   optically active (R or S)-3-(4-chlorobenzylamino)butyric acid,-   optically active (R or S)-3-(4-fluorobenzylamino)butyric acid,-   optically active (R or S)-3-(4-methoxybenzylamino)acetic acid,-   optically active (R or S)-3-(4-hydroxybenzyl)aminoacetic acid,-   optically active (R or S)-3-(4-methylbenzyl)aminobutyric acid,-   optically active (R or S)-3-(3,4-dimethoxybenzyl)aminobutyric acid,-   optically active (R or S)-3-(3,4-methylenedioxybenzyl)aminobutyric    acid,-   optically active (R or S)-3-(4-nitrobenzyl)aminobutyric acid,-   optically active (R or S)-3-(1-naphthylmethyl)aminobutyric acid,-   optically active (R or S)-3-(1-phenylethyl)aminobutyric acid,-   optically active (R or S)-3-(1-(1-naphthyl)ethyl)aminobutyric acid,-   optically active (R or S)-3-diphenylmethylaminobutyric acid,-   optically active (R or S)-3-benzylaminopentanoic acid,-   optically active (R or S)-3-(4-chlorobenzylamino)pentanoic acid-   optically active (R or S)-3-(4-methoxybenzylamino)pentanoic acid,-   optically active (R or S)-3-(4-nitrobenzylamino)pentanoic acid,-   optically active (R or S)-3-benzylaminohexanoic acid,-   optically active (R or S)-3-benzylamino-4-methylpentanoic acid,-   optically active (R or S)-3-(2-methylbenzyl)-4-methylpentanoic acid,-   optically active (R or S)-3-(4-methylbenzyl)-4-methylpentanoic acid,-   optically active (R or S)-3-(2-methoxybenzyl)-4-methylpentanoic    acid,-   optically active (R or S)-3-(4-methoxybenzyl)amino-4-methylpentanoic    acid,-   optically active (R or S)-3-(2-chlorobenzyl)amino-4-methylpentanoic    acid,-   optically active (R or S)-3-(4-chlorobenzyl)amino-4-methylpentanoic    acid,-   optically active (R or S)-3-(4-nitrobenzyl)amino-4-methylpentanoic    acid,-   optically active (R or S)-3-(2-methoxybenzyl)amino-4-methylpentanoic    acid,-   optically active (R or S)-3-(4-methoxybenzyl)amino-4-methylpentanoic    acid,-   optically active (R or    S)-3-(3,4-dimethoxybenzyl)amino-4-methylpentanoic acid,-   optically active (R or    S)-3-(3,4-methylenedioxybenzyl)amino-4-methylpentanoic acid,-   optically active (R or S)-3-benzylamino-4-chlorobutyric acid,-   optically active (R or S)-3-benzylamino-4-hydroxybutyric acid,-   optically active (R or S)-3-benzylamino-3-phenylpropionic acid,-   optically active (R or S)-3-(4-methoxybenzylamino)-3-phenylpropionic    acid,-   optically active (R or S)-3-(4-hydroxybenzyl)amino-3-phenylpropionic    acid,-   optically active (R or    S)-3-(3,4-dimethoxybenzyl)amino-3-phenylpropionic acid,-   optically active (R or    S)-3-(3,4-methylenedioxybenzyl)amino-3-phenylpropionic acid,-   optically active (R or S)-3-(1-phenylethyl)amino-3-phenylpropionic    acid,-   optically active (R or    S)-3-(1-(1-naphthyl)ethyl)amino-3-phenylpropionic acid,-   optically active (R or S)-3-diphenylmethylamino-3-phenylpropionic    acid,-   optically active (R or S)-3-tritylamino-3-phenylpropionic acid,-   optically active (R or S)-3-benzylamino-3-(2-fluorophenyl)propionic    acid,-   optically active (R or S)-3-benzylamino-3-(4-fluorophenyl)propionic    acid,-   optically active (R or    S)-3-diphenylmethylamino-3-(4-fluorophenyl)propionic acid,-   optically active (R or    S)-3-benzylamino-3-(2-chlorophenyl)phenylpropionic acid,-   optically active (R or    S)-3-benzylamino-3-(4-chlorophenyl)phenylpropionic acid,-   optically active (R or S)-3-benzylamino-3-(4-hydroxyphenyl)propionic    acid,-   optically active (R or S)-3-benzylamino-3-(2-hydroxyphenyl)propionic    acid,-   optically active (R or S)-3-benzylamino-3-(2-methoxyphenyl)propionic    acid,-   optically active (R or S)-3-benzylamino-3-(4-methoxyphenyl)propionic    acid,-   optically active (R or    S)-3-diphenylmethylamino-3-(4-methoxyphenyl)propionic acid,-   optically active (R or    S)-3-benzylamino-3-(3,4-dimethoxyphenyl)propionic acid,-   optically active (R or    S)-3-diphenylmethylamino-3-(3,4-dimethoxyphenyl)propionic acid,-   optically active (R or    S)-3-benzylamino-3-(3,4-methylenedioxyphenyl)propionic acid,-   optically active (R or    S)-3-diphenylmethylamino-3-(3,4-methylenedioxyphenyl)propionic acid,-   optically active (R or S)-3-benzylamino-3-(4-tolyl)propionic acid,-   optically active (R or S)-3-diphenylmethylamino-3-(4-tolyl)propionic    acid,-   optically active (R or S)-3-benzylamino-3-(2-tolyl)propionic acid,-   optically active (R or S)-3-benzylamino-4-phenylbutyric acid,-   optically active (R or S)-3-benzylamino-4-(4-fluorophenyl)butyric    acid,-   optically active (R or S)-3-benzylamino-4-(2-fluorophenyl)butyric    acid,-   optically active (R or S)-3-benzylamino-4-(4-chlorophenyl)butyric    acid,-   optically active (R or S)-3-benzylamino-4-(4-methoxyphenyl)butyric    acid,-   optically active (R or S)-3-benzylamino-4-(2-methoxyphenyl)butyric    acid,-   optically active (R or    S)-3-benzylamino-4-(3,4-dimethoxyphenyl)butyric acid,-   optically active (R or S)-3-benzylamino-4-(4-hydroxyphenyl)butyric    acid,-   optically active (R or S)-3-benzylamino-5-phenylpentanoic acid,-   optically active (R or S)-3-benzylamino-5-(4-fluorophenyl)pentanoic    acid,-   optically active (R or S)-3-benzylamino-5-(4-chlorophenyl)pentanoic    acid,-   optically active (R or S)-3-benzylamino-5-(2-fluorophenyl)pentanoic    acid,-   optically active (R or S)-3-benzylamino-5-(4-methoxyphenyl)pentanoic    acid,-   optically active (R or S)-3-benzylamino-5-(2-methoxyphenyl)pentanoic    acid,-   optically active (R or    S)-3-benzylamino-5-(3,4-dimethoxyphenyl)pentanoic acid,-   optically active (R or S)-3-benzhydrylamino-5-phenylpentanoic acid,-   optically active (R or S)-3-(1-phenylethyl)amino-4-chlorobutyric    acid,-   optically active (R or S)-3-benzhydrylamino-4-hydroxybutyric acid,-   optically active (R or S)-3-benzhydrylaminopentanoic acid,-   optically active (R or S)-3-(1-phenylethyl)amino-4-methylpentanoic    acid,-   optically active (R or S)-3-benzhydrylamino-4-methylpentanoic acid,    more preferably-   optically active (R or S)-3-benzylaminobutyric acid,-   optically active (R or S)-3-benzylamino-3-phenylpropionic acid,-   optically active (R or S)-3-benzylamino-3-(4-tolyl)propionic acid,-   optically active (R or S)-3-benzylamino-3-(4-fluorophenyl)propionic    acid,-   optically active (R or    S)-3-benzylamino-3-(3,4-methylenedioxyphenyl)propionic acid,-   optically active (R or    S)-3-benzylamino-3-(3,4-methylenedioxyphenyl)propionic acid,-   optically active (R or S)-3-benzylaminopentanoic acid,-   optically active (R or S)-3-benzylaminohexanoic acid, and-   optically active (R or S)-3-benzylamino-4-methylpentanoic acid.

Specific examples of unreacted Compound (III-a) (having reverse stericabsolute configration to that of Compound (II-a)) which was not reactedin the hydrolysis reaction of the present invention may include, forexample,

-   optically active methyl (S or R)-3-benzylaminobutyrate,-   optically active ethyl (S or R)-3-benzylaminobutyrate,-   optically active n-propyl (S or R)-3-benzylaminobutyrate,-   optically active n-butyl (S or R)-3-benzylaminobutyrate,-   optically active n-octyl (S or R)-3-benzylaminobutyrate,-   optically active 2-chloroethyl (S or R)-3-benzylaminobutyrate,-   optically active 2,2,2-trichloroethyl (S or    R)-3-benzylaminobutyrate,-   optically active 2,2,2-trifluoroethyl (S or    R)-3-benzylaminobutyrate,-   optically active 2-cyanoethyl (S or R)-3-benzylaminobutyrate,-   optically active methyl (S or R)-3-(4-chlorobenzylamino)butyrate,-   optically active methyl (S or R)-3-(4-fluorobenzylamino)butyrate,-   optically active methyl (S or R)-3-(4-methoxybenzylamino)acetate,-   optically active methyl (S or R)-3-(4-hydroxybenzyl)aminoacetate,-   optically active methyl (S or R)-3-(4-methylbenzyl)aminobutyrate,-   optically active methyl (S or    R)-3-(3,4-dimethoxybenzyl)aminobutyrate,-   optically active methyl (S or    R)-3-(3,4-methylenedioxybenzyl)aminobutyrate,-   optically active methyl (S or R)-3-(4-nitrobenzyl)aminobutyrate,-   optically active methyl (S or R)-3-(1-naphthylmethyl)aminobutyrate,-   optically active methyl (S or R)-3-(1-phenylethyl)aminobutyrate,-   optically active methyl (S or    R)-3-(1-(2-chlorophenyl)ethyl)aminobutyrate,-   optically active methyl (S or    R)-3-(1-(1-naphthyl)ethyl)aminobutyrate,-   optically active methyl (S or R)-3-diphenylmethylaminobutyrate,-   optically active methyl (S or R)-3-tritylaminobutyrate,-   optically active methyl (S or R)-3-benzylaminopentanoate,-   optically active ethyl (S or R)-3-benzylaminopentanoate,-   optically active 2,2,2-trifluoroethyl (S or    R)-3-benzylaminopentanoate,-   optically active methyl (S or R)-3-(4-chlorobenzylamino)pentanoate,-   optically active methyl (S or R)-3-(4-methoxybenzylamino)pentanoate,-   optically active ethyl (S or R)-3-(4-nitrobenzylamino)pentanoate,-   optically active methyl (S or R)-3-benzylaminohexanoate,-   optically active ethyl (S or R)-3-benzylaminohexanoate,-   optically active 2,2,2-trichloroethyl (S or    R)-3-benzylaminohexanoate,-   optically active 2,2,2-trifluoroethyl (S or    R)-3-benzylaminohexanoate,-   optically active methyl (S or R)-3-benzylamino-4-methylpentanoate,-   optically active ethyl (S or R)-3-benzylamino-4-methylpentanoate,-   optically active n-propyl (S or R)-3-benzylamino-4-methylpentanoate,-   optically active n-butyl (S or R)-3-benzylamino-4-methylpentanoate,-   optically active n-pentyl (S or R)-3-benzylamino-4-methylpentanoate,-   optically active n-octyl (S or R)-3-benzylamino-4-methylpentanoate,-   optically active 2-chloroethyl (S or    R)-3-benzylamino-4-methylpentanoate,-   optically active 2,2,2-trichloroethyl (S or    R)-3-benzylamino-4-methylpentanoate,-   optically active 2,2,2-trifluoroethyl (S or    R)-3-benzylamino-4-methylpentanoate,-   optically active methyl (S or    R)-3-(2-methylbenzyl)-4-methylpentanoate,-   optically active methyl (S or    R)-3-(3-methylbenzyl)-4-methylpentanoate,-   optically active methyl (S or    R)-3-(4-methylbenzyl)-4-methylpentanoate,-   optically active methyl (S or    R)-3-(2-methoxybenzyl)-4-methylpentanoate,-   optically active methyl (S or    R)-3-(3-methoxybenzyl)amino-4-methylpentanoate,-   optically active methyl (S or    R)-3-(4-methoxybenzyl)amino-4-methylpentanoate,-   optically active butyl (S or    R)-3-(2-chlorobenzyl)amino-4-methylpentanoate,-   optically active ethyl (S or    R)-3-(3-chlorobenzyl)amino-4-methylpentanoate,-   optically active methyl (S or    R)-3-(4-chlorobenzyl)amino-4-methylpentanoate,-   optically active methyl (S or    R)-3-(2-bromobenzyl)amino-4-methylpentanoate,-   optically active methyl (S or    R)-3-(3-bromobenzyl)amino-4-methylpentanoate,-   optically active ethyl (S or    R)-3-(4-bromobenzyl)amino-4-methylpentanoate,-   optically active methyl (S or    R)-3-(2-fluorobenzyl)amino-4-methylpentanoate,-   optically active methyl (S or    R)-3-(2-nitrobenzyl)amino-4-methylpentanoate,-   optically active methyl (S or    R)-3-(4-nitrobenzyl)amino-4-methylpentanoate,-   optically active methyl (S or    R)-3-(2-methoxybenzyl)amino-4-methylpentanoate,-   optically active methyl (S or    R)-3-(3-methoxybenzyl)amino-4-methylpentanoate,-   optically active methyl (S or    R)-3-(4-methoxybenzyl)amino-4-methylpentanoate,-   optically active methyl (S or    R)-3-(3,4-dimethoxybenzyl)amino-4-methylpentanoate,-   optically active methyl (S or    R)-3-(3,4-methylenedioxybenzyl)amino-4-methylpentanoate,-   optically active methyl (S or R)-3-benzylamino-4-chlorobutyrate,-   optically active ethyl (S or R)-3-benzylamino-4-chlorobutyrate,-   optically active methyl (S or R)-3-benzylamino-4-hydroxybutyrate,-   optically active ethyl (S or R)-3-benzylamino-4-hydroxybutyrate,-   optically active methyl (S or R)-3-benzylamino-3-phenylpropionate,-   optically active ethyl (S or R)-3-benzylamino-3-phenylpropionate,-   optically active n-propyl (S or R)-3-benzylamino-3-phenylpropionate,-   optically active n-butyl (S or R)-3-benzylamino-3-phenylpropionate,-   optically active n-octyl (S or R)-3-benzylamino-3-phenylpropionate,-   optically active 2-chloroethyl (S or    R)-3-benzylamino-3-phenylpropionate,-   optically active 2,2,2-trichloroethyl (S or    R)-3-benzylamino-3-phenylpropionate,-   optically active 2,2,2-trifluoroethyl (S or    R)-3-benzylamino-3-phenylpropionate,-   optically active 2-cyanoethyl (S or    R)-3-benzylamino-3-phenylpropionate,-   optically active methyl (S or    R)-3-(4-methoxybenzylamino)-3-phenylpropionate,-   optically active methyl (S or    R)-3-(4-hydroxybenzyl)amino-3-phenylpropionate,-   optically active methyl (S or    R)-3-(4-methylbenzyl)amino-3-phenylpropionate,-   optically active methyl (S or    R)-3-(3,4-dimethoxybenzyl)amino-3-phenylpropionate,-   optically active methyl (S or    R)-3-(3,4-methylenedioxybenzyl)amino-3-phenylpropionate,-   optically active methyl (S or    R)-3-(4-nitrobenzyl)amino-3-phenylpropionate,-   optically active methyl (S or    R)-3-(1-phenylethyl)amino-3-phenylpropionate,-   optically active methyl (S or    R)-3-(1-(1-naphthyl)ethyl)amino-3-phenylpropionate,-   optically active methyl (S or    R)-3-diphenylmethylamino-3-phenylpropionate,-   optically active methyl (S or R)-3-tritylamino-3-phenylpropionate,-   optically active methyl (S or    R)-3-benzylamino-3-(2-fluorophenyl)propionate,-   optically active methyl (S or    R)-3-benzylamino-3-(4-fluorophenyl)propionate,-   optically active ethyl (S or    R)-3-benzylamino-3-(4-fluorophenyl)propionate,-   optically active methyl (S or    R)-3-diphenylmethylamino-3-(4-fluorophenyl)propionate,-   optically active methyl (S or    R)-3-benzylamino-3-(2-chlorophenyl)phenylpropionate,-   optically active methyl (S or    R)-3-benzylamino-3-(4-chlorophenyl)phenylpropionate,-   optically active methyl (S or    R)-3-benzylamino-3-(4-bromophenyl)propionate,-   optically active ethyl (S or    R)-3-benzylamino-3-(4-iodophenyl)propionate,-   optically active methyl (S or    R)-3-benzylamino-3-(4-hydroxyphenyl)propionate,-   optically active ethyl (S or    R)-3-benzylamino-3-(2-hydroxyphenyl)propionate,-   optically active methyl (S or    R)-3-benzylamino-3-(2-methoxyphenyl)propionate,-   optically active methyl (S or    R)-3-benzylamino-3-(4-methoxyphenyl)propionate,-   optically active ethyl (S or    R)-3-benzylamino-3-(4-methoxyphenyl)propionate,-   optically active methyl (S or    R)-3-diphenylmethylamino-3-(4-methoxyphenyl)propionate,-   optically active methyl (S or    R)-3-benzylamino-3-(3,4-dimethoxyphenyl)propionate,-   optically active ethyl (S or    R)-3-benzylamino-3-(3,4-dimethoxyphenyl)propionate,-   optically active methyl (S or    R)-3-diphenylmethylamino-3-(3,4-dimethoxyphenyl)propionate,-   optically active methyl (S or    R)-3-benzylamino-3-(3,4-methylenedioxyphenyl)propionate,-   optically active ethyl (S or    R)-3-benzylamino-3-(3,4-methylenedioxyphenyl)propionate,-   optically active ethyl (S or    R)-3-diphenylmethylamino-3-(3,4-methylenedioxyphenyl)propionate,-   optically active methyl (S or    R)-3-benzylamino-3-(4-tolyl)propionate,-   optically active ethyl (S or R)-3-benzylamino-3-(4-tolyl)propionate,-   optically active methyl (S or    R)-3-diphenylmethylamino-3-(4-tolyl)propionate,-   optically active methyl (S or    R)-3-benzylamino-3-(2-tolyl)propionate,-   optically active methyl (S or R)-3-benzylamino-4-phenylbutyrate,-   optically active ethyl (S or R)-3-benzylamino-4-phenylbutyrate,-   optically active methyl (S or    R)-3-benzylamino-4-(4-fluorophenyl)butyrate,-   optically active methyl (S or    R)-3-benzylamino-4-(2-fluorophenyl)butyrate,-   optically active methyl (S or    R)-3-benzylamino-4-(4-chlorophenyl)butyrate,-   optically active methyl (S or    R)-3-benzylamino-4-(4-iodophenyl)butyrate,-   optically active methyl (S or    R)-3-benzylamino-4-(4-methoxyphenyl)butyrate,-   optically active methyl (S or    R)-3-benzylamino-4-(2-methoxyphenyl)butyrate,-   optically active methyl (S or    R)-3-benzylamino-4-(3,4-dimethoxyphenyl)butyrate,-   optically active methyl (S or    R)-3-benzylamino-4-(4-hydroxyphenyl)butyrate,-   optically active methyl (S or R)-3-benzylamino-5-phenylpentanoate,-   optically active methyl (S or    R)-3-benzylamino-5-(4-fluorophenyl)pentanoate,-   optically active methyl (S or    R)-3-benzylamino-5-(4-chlorophenyl)pentanoate,-   optically active methyl (S or    R)-3-benzylamino-5-(2-fluorophenyl)pentanoate,-   optically active methyl (S or    R)-3-benzylamino-5-(4-methoxyphenyl)pentanoate,-   optically active methyl (S or    R)-3-benzylamino-5-(2-methoxyphenyl)pentanoate,-   optically active methyl (S or    R)-3-benzylamino-5-(3,4-dimethoxyphenyl)pentanoate,-   optically active methyl (S or    R)-3-(1-phenylethyl)amino-5-phenylpentanoate,-   optically active methyl (S or    R)-3-benzhydrylamino-5-phenylpentanoate,-   optically active methyl (S or    R)-3-(1-phenylethyl)amino-4-chlorobutyrate,-   optically active ethyl (S or R)-3-benzhydrylamino-4-hydroxybutyrate,-   optically active ethyl (S or    R)-3-(1-phenylethyl)amino-4-hydroxybutyrate,-   optically active ethyl (S or R)-3-benzhydrylamino-4-hydroxybutyrate,-   optically active methyl (S or R)-3-(1-phenylethyl)aminobutyrate,-   optically active methyl (S or R)-3-benzhydrylaminopentanoate,-   optically active methyl (S or    R)-3-(1-phenylethyl)amino-4-methylpentanoate,-   optically active ethyl (S or    R)-3-benzhydrylamino-4-methylpentanoate,-   optically active methyl (S or R)-3-(1-naphthylmethyl)aminobutyrate,-   optically active methyl (S or R)-3-(2-naphthylmethyl)aminobutyrate,-   optically active methyl (S or    R)-3-(2-naphthylmethyl)aminopentanoate,-   optically active methyl (S or    R)-3-(2-naphthylmethyl)amino-4-methylpentanoate,-   optically active methyl (S or    R)-3-(1-(1-naphthyl)ethylamino-4-methylpentanoate,    and the like, preferably-   optically active methyl (S or R)-3-benzylaminobutyrate,-   optically active ethyl (S or R)-3-benzylaminobutyrate,-   optically active n-octyl (S or R)-3-benzylaminobutyrate,-   optically active 2-chloroethyl (S or R)-3-benzylaminobutyrate,-   optically active 2,2,2-trichloroethyl (S or    R)-3-benzylaminobutyrate,-   optically active 2,2,2-trifluoroethyl (S or    R)-3-benzylaminobutyrate,-   optically active methyl (S or R)-3-(4-chlorobenzylamino)butyrate,-   optically active methyl (S or R)-3-(4-fluorobenzylamino)butyrate,-   optically active methyl (S or R)-3-(4-methoxybenzylamino)acetate,-   optically active methyl (S or R)-3-(4-hydroxybenzyl)aminoacetate,-   optically active methyl (S or R)-3-(4-methylbenzyl)aminobutyrate,-   optically active methyl (S or    R)-3-(3,4-dimethoxybenzyl)aminobutyrate,-   optically active methyl (S or    R)-3-(3,4-methylenedioxybenzyl)aminobutyrate,-   optically active methyl (S or R)-3-(4-nitrobenzyl)aminobutyrate,-   optically active methyl (S or R)-3-(1-naphthylmethyl)aminobutyrate,-   optically active methyl (S or R)-3-(1-phenylethyl)aminobutyrate,-   optically active methyl (S or    R)-3-(1-(1-naphthyl)ethyl)aminobutyrate,-   optically active methyl (S or R)-3-diphenylmethylaminobutyrate,-   optically active methyl (S or R)-3-benzylaminopentanoate,-   optically active ethyl (S or R)-3-benzylaminopentanoate,-   optically active methyl (S or R)-3-(4-chlorobenzylamino)pentanoate-   optically active methyl (S or R)-3-(4-methoxybenzylamino)pentanoate,-   optically active ethyl (S or R)-3-(4-nitrobenzylamino)pentanoate,-   optically active methyl (S or R)-3-benzylaminohexanoate,-   optically active ethyl (S or R)-3-benzylaminohexanoate,-   optically active 2,2,2-trifluoroethyl (S or    R)-3-benzylaminohexanoate,-   optically active methyl (S or R)-3-benzylamino-4-methylpentanoate,-   optically active ethyl (S or R)-3-benzylamino-4-methylpentanoate,-   optically active n-octyl (S or R)-3-benzylamino-4-methylpentanoate,-   optically active 2-chloroethyl (S or    R)-3-benzylamino-4-methylpentanoate,-   optically active 2,2,2-trichloroethyl (S or    R)-3-benzylamino-4-methylpentanoate,-   optically active 2,2,2-trifluoroethyl (S or    R)-3-benzylamino-4-methylpentanoate,-   optically active methyl (S or    R)-3-(2-methylbenzyl)-4-methylpentanoate,-   optically active methyl (S or    R)-3-(4-methylbenzyl)-4-methylpentanoate,-   optically active methyl (S or    R)-3-(2-methoxybenzyl)-4-methylpentanoate,-   optically active methyl (S or    R)-3-(4-methoxybenzyl)amino-4-methylpentanoate,-   optically active butyl (S or    R)-3-(2-chlorobenzyl)amino-4-methylpentanoate,-   optically active methyl (S or    R)-3-(4-chlorobenzyl)amino-4-methylpentanoate,-   optically active methyl (S or    R)-3-(4-nitrobenzyl)amino-4-methylpentanoate,-   optically active methyl (S or    R)-3-(2-methoxybenzyl)amino-4-methylpentanoate,-   optically active methyl (S or    R)-3-(4-methoxybenzyl)amino-4-methylpentanoate,-   optically active methyl (S or    R)-3-(3,4-dimethoxybenzyl)amino-4-methylpentanoate,-   optically active methyl (S or    R)-3-(3,4-methylenedioxybenzyl)amino-4-methylpentanoate,-   optically active methyl (S or R)-3-benzylamino-4-chlorobutyrate,-   optically active ethyl (S or R)-3-benzylamino-4-chlorobutyrate,-   optically active methyl (S or R)-3-benzylamino-4-hydroxybutyrate,-   optically active methyl (S or R)-3-benzylamino-3-phenylpropionate,-   optically active ethyl (S or R)-3-benzylamino-3-phenylpropionate,-   optically active 2-chloroethyl (S or    R)-3-benzylamino-3-phenylpropionate,-   optically active 2,2,2-trichloroethyl (S or    R)-3-benzylamino-3-phenylpropionate,-   optically active 2,2,2-trifluoroethyl (S or    R)-3-benzylamino-3-phenylpropionate,-   optically active 2-cyanoethyl (S or    R)-3-benzylamino-3-phenylpropionate,-   optically active methyl (S or    R)-3-(4-methoxybenzylamino)-3-phenylpropionate,-   optically active methyl (S or    R)-3-(4-hydroxybenzyl)amino-3-phenylpropionate,-   optically active methyl (S or    R)-3-(3,4-dimethoxybenzyl)amino-3-phenylpropionate,-   optically active methyl (S or    R)-3-(3,4-methylenedioxybenzyl)amino-3-phenylpropionate,-   optically active methyl (S or    R)-3-(1-phenylethyl)amino-3-phenylpropionate,-   optically active methyl (S or    R)-3-(1-(1-naphthyl)ethyl)amino-3-phenylpropionate,-   optically active methyl (S or    R)-3-diphenylmethylamino-3-phenylpropionate,-   optically active methyl (S or R)-3-tritylamino-3-phenylpropionate,-   optically active methyl (S or    R)-3-benzylamino-3-(2-fluorophenyl)propionate,-   optically active methyl (S or    R)-3-benzylamino-3-(4-fluorophenyl)propionate,-   optically active ethyl (S or    R)-3-benzylamino-3-(4-fluorophenyl)propionate,-   optically active methyl (S or    R)-3-diphenylmethylamino-3-(4-fluorophenyl)propionate,-   optically active methyl (S or    R)-3-benzylamino-3-(2-chlorophenyl)phenylpropionate,-   optically active methyl (S or    R)-3-benzylamino-3-(4-chlorophenyl)phenylpropionate,-   optically active methyl (S or    R)-3-benzylamino-3-(4-hydroxyphenyl)propionate,-   optically active ethyl (S or    R)-3-benzylamino-3-(2-hydroxyphenyl)propionate,-   optically active methyl (S or    R)-3-benzylamino-3-(2-methoxyphenyl)propionate,-   optically active methyl (S or    R)-3-benzylamino-3-(4-methoxyphenyl)propionate,-   optically active ethyl (S or    R)-3-benzylamino-3-(4-methoxyphenyl)propionate,-   optically active methyl (S or    R)-3-diphenylmethylamino-3-(4-methoxyphenyl)propionate,-   optically active methyl (S or    R)-3-benzylamino-3-(3,4-dimethoxyphenyl)propionate,-   optically active ethyl (S or    R)-3-benzylamino-3-(3,4-dimethoxyphenyl)propionate,-   optically active methyl (S or    R)-3-diphenylmethylamino-3-(3,4-dimethoxyphenyl)propionate,-   optically active methyl (S or    R)-3-benzylamino-3-(3,4-methylenedioxyphenyl)propionate,-   optically active ethyl (S or    R)-3-benzylamino-3-(3,4-methylenedioxyphenyl)propionate,-   optically active ethyl (S or    R)-3-diphenylmethylamino-3-(3,4-methylenedioxyphenyl)propionate,-   optically active methyl (S or    R)-3-benzylamino-3-(4-tolyl)propionate,-   optically active ethyl (S or R)-3-benzylamino-3-(4-tolyl)propionate,-   optically active methyl (S or    R)-3-diphenylmethylamino-3-(4-tolyl)propionate,-   optically active methyl (S or    R)-3-benzylamino-3-(2-tolyl)propionate,-   optically active methyl (S or R)-3-benzylamino-4-phenylbutyrate,-   optically active methyl (S or    R)-3-benzylamino-4-(4-fluorophenyl)butyrate,-   optically active methyl (S or    R)-3-benzylamino-4-(2-fluorophenyl)butyrate,-   optically active methyl (S or    R)-3-benzylamino-4-(4-chlorophenyl)butyrate,-   optically active methyl (S or    R)-3-benzylamino-4-(4-methoxyphenyl)butyrate,-   optically active methyl (S or    R)-3-benzylamino-4-(2-methoxyphenyl)butyrate,-   optically active methyl (S or    R)-3-benzylamino-4-(3,4-dimethoxyphenyl)butyrate,-   optically active methyl (S or    R)-3-benzylamino-4-(4-hydroxyphenyl)butyrate,-   optically active methyl (S or R)-3-benzylamino-5-phenylpentanoate,-   optically active methyl (S or    R)-3-benzylamino-5-(4-fluorophenyl)pentanoate,-   optically active methyl (S or    R)-3-benzylamino-5-(4-chlorophenyl)pentanoate,-   optically active methyl (S or    R)-3-benzylamino-5-(2-fluorophenyl)pentanoate,-   optically active methyl (S or    R)-3-benzylamino-5-(4-methoxyphenyl)pentanoate,-   optically active methyl (S or    R)-3-benzylamino-5-(2-methoxyphenyl)pentanoate,-   optically active methyl (S or    R)-3-benzylamino-5-(3,4-dimethoxyphenyl)pentanoate,-   optically active methyl (S or    R)-3-benzhydrylamino-5-phenylpentanoate,-   optically active methyl (S or    R)-3-(1-phenylethyl)amino-4-chlorobutyrate,-   optically active ethyl (S or R)-3-benzhydrylamino-4-hydroxybutyrate,-   optically active methyl (S or R)-3-benzhydrylaminopentanoate,-   optically active methyl (S or    R)-3-(1-phenylethyl)amino-4-methylpentanoate,-   optically active ethyl (S or    R)-3-benzhydrylamino-4-methylpentanoate,    more preferably-   optically active methyl (S or R)-3-benzylaminobutyrate,-   optically active ethyl (S or R)-3-benzylaminobutyrate,-   optically active methyl (S or R)-3-benzylamino-3-phenylpropionate-   optically active ethyl (S or R)-3-benzylamino-3-phenylpropionate-   optically active methyl (S or    R)-3-benzylamino-3-(4-tolyl)propionate,-   optically active ethyl (S or R)-3-benzylamino-3-(4-tolyl)propionate,-   optically active methyl (S or    R)-3-benzylamino-3-(4-fluorophenyl)propionate-   optically active methyl (S or    R)-3-benzylamino-3-(3,4-methylenedioxyphenyl)propionate,-   optically active ethyl (S or    R)-3-benzylamino-3-(3,4-methylenedioxyphenyl)propionate,-   optically active methyl (S or R)-3-benzylaminopentanoate,-   optically active ethyl (S or R)-3-benzylaminopentanoate,-   optically active methyl (S or R)-3-benzylaminohexanoate,-   optically active ethyl (S or R)-3-benzylaminohexanoate,-   optically active methyl (S or R)-3-benzylamino-4-methylpentanoate,-   optically active ethyl (S or R)-3-benzylamino-4-methylpentanoate.

Also, specific examples of Compound (II-b) obtained by the hydrolysisreaction of the present invention may include, for example,

-   optically active (R or S) 1-benzyl-2-homopipecolic acid,-   optically active (R or S) 1-(4-methylbenzyl)-2-homopipecolic acid,-   optically active (R or S) 1-(hydroxybenzyl)-2-homopipecolic acid,-   optically active (R or S) 1-(3,4-dihydroxybenzyl)-2-homopipecolic    acid,-   optically active (R or S) 1-(4-chlorobenzyl)-2-homopipecolic acid,-   optically active (R or S) 1-(4-fluorobenzyl)-2-homopipecolic acid,-   optically active (R or S) 1-(4-methoxybenzyl)-2-homopipecolic acid,-   optically active (R or S) 1-(3,4-dimethoxybenzyl)-2-homopipecolic    acid,-   optically active (R or S)    1-(3,4-methylenedioxybenzyl)-2-homopipecolic acid,-   optically active (R or S) 1-(4-nitrobenzyl)-2-homopipecolic acid,-   optically active (R or S) 1-(1-naphthylmethyl)-2-homopipecolic acid,-   optically active (R or S) 1-(2-naphthylmethyl)-2-homopipecolic acid,-   optically active (R or S) 1-(1-phenylethyl)-2-homopipecolic acid,-   optically active (R or S)    1-(1-(2-chlorophenyl)ethyl)-2-homopipecolic acid,-   optically active (R or S) 1-(1-(1-naphthyl)ethyl)-2-homopipecolic    acid,-   optically active (R or S) 1-diphenylmethyl-2-homopipecolic acid,-   optically active (R or S) 1-trityl-2-homopipecolic acid,-   optically active (R or S)    1-di(4-methoxyphenyl)methyl-2-homopipecolic acid,    and the like, preferably-   optically active (R or S) 1-benzyl-2-homopipecolic acid,-   optically active (R or S) 1-(4-methylbenzyl)-2-homopipecolic acid,-   optically active (R or S) 1-(hydroxybenzyl)-2-homopipecolic acid,-   optically active (R or S) 1-(4-chlorobenzyl)-2-homopipecolic acid,-   optically active (R or S) 1-(4-methoxybenzyl)-2-homopipecolic acid,-   optically active (R or S) 1-(4-nitrobenzyl)-2-homopipecolic acid,-   optically active (R or S) 1-(1-naphthylmethyl)-2-homopipecolic acid,-   optically active (R or S) 1-(1-phenylethyl)-2-homopipecolic acid,-   optically active (R or S) 1-(1-(1-naphthyl)ethyl)-2-homopipecolic    acid,-   optically active (R or S) 1-diphenylmethyl-2-homopipecolic acid,    more preferably-   optically active (R or S) 1-benzyl-2-homopipecolic acid,-   optically active (R or S) 1-(4-methoxybenzyl)-2-homopipecolic acid,-   optically active (R or S) 1-(1-phenylethyl)-2-homopipecolic acid,-   optically active (R or S) 1-diphenylmethyl-2-homopipecolic acid.

Specific examples of the unreacted Compound (III-b) (having reversesteric absolute configration to that of Compound (II-b).) which was notreacted in the hydrolysis reaction of the present invention may include,for example,

-   optically active methyl (S or R) 1-benzyl-2-homopipecolate,-   optically active ethyl (S or R) 1-benzyl-2-homopipecolate,-   optically active n-butyl (S or R) 1-benzyl-2-homopipecolate,-   optically active n-octyl (S or R) 1-benzyl-2-homopipecolate,-   optically active 2-chloroethyl (S or R) 1-benzyl-2-homopipecolate,-   optically active 2,2,2-trichloroethyl (S or R)    1-benzyl-2-homopipecolate,-   optically active 2,2,2-trifluoroethyl (S or R)    1-benzyl-2-homopipecolate,-   optically active 2-cyano (S or R) 1-benzyl-2-homopipecolate,-   optically active methyl (S or R)    1-(4-methylbenzyl)-2-homopipecolate,-   optically active ethyl (S or R) 1-(hydroxybenzyl)-2-homopipecolate,-   optically active methyl (S or R)    1-(3,4-dihydroxybenzyl)-2-homopipecolate,-   optically active methyl (S or R)    1-(4-chlorobenzyl)-2-homopipecolate,-   optically active ethyl (S or R) 1-(4-fluorobenzyl)-2-homopipecolate,-   optically active methyl (S or R)    1-(4-methoxybenzyl)-2-homopipecolate,-   optically active methyl (S or R)    1-(3,4-dimethoxybenzyl)-2-homopipecolate,-   optically active methyl (S or R)    1-(3,4-methylenedioxybenzyl)-2-homopipecolate,-   optically active methyl (S or R) 1-(4-nitrobenzyl)-2-homopipecolate,-   optically active methyl (S or R)    1-(1-naphthylmethyl)-2-homopipecolate,-   optically active methyl (S or R)    1-(2-naphthylmethyl)-2-homopipecolate,-   optically active methyl (S or R) 1-(1-phenylethyl)-2-homopipecolate,-   optically active methyl (S or R)    1-(1-(2-chlorophenyl)ethyl)-2-homopipecolate,-   optically active methyl (S or R)    1-(1-(1-naphthyl)ethyl)-2-homopipecolate,-   optically active methyl (S or R) 1-diphenylmethyl-2-homopipecolate,-   optically active 2,2,2-trifluoroethyl (S or R)    1-trityl-2-homopipecolate,-   optically active methyl (S or R)    1-di(4-methoxyphenyl)methyl-2-homopipecolate,    and the like, preferably-   optically active methyl (S or R) 1-benzyl-2-homopipecolate,-   optically active ethyl (S or R) 1-benzyl-2-homopipecolate,-   optically active n-octyl (S or R) 1-benzyl-2-homopipecolate,-   optically active 2-chloroethyl (S or R) 1-benzyl-2-homopipecolate,-   optically active 2,2,2-trichloroethyl (S or R)    1-benzyl-2-homopipecolate,-   optically active 2,2,2-trifluoroethyl (S or R)    1-benzyl-2-homopipecolate,-   optically active methyl (S or R)    1-(4-methylbenzyl)-2-homopipecolate,-   optically active ethyl (S or R) 1-(hydroxybenzyl)-2-homopipecolate,-   optically active methyl (S or R)    1-(4-chlorobenzyl)-2-homopipecolate,-   optically active methyl (S or R)    1-(4-methoxybenzyl)-2-homopipecolate,-   optically active methyl (S or R) 1-(4-nitrobenzyl)-2-homopipecolate,-   optically active methyl (S or R)    1-(1-naphthylmethyl)-2-homopipecolate,-   optically active methyl (S or R) 1-(1-phenylethyl)-2-homopipecolate,-   optically active methyl (S or R)    1-(1-(1-naphthyl)ethyl)-2-homopipecolate,-   optically active methyl (S or R) 1-diphenylmethyl-2-homopipecolate,    more preferably-   optically active methyl (S or R) 1-benzyl-2-homopipecolate,-   optically active ethyl (S or R) 1-benzyl-2-homopipecolate,-   optically active methyl (S or R)    1-(4-methoxybenzyl)-2-homopipecolate,-   optically active methyl (S or R) 1-(1-phenylethyl)-2-homopipecolate,-   optically active methyl (S or R) 1-diphenylmethyl-2-homopipecolate.

EXAMPLE

Next, the present invention is explained more specifically by referringto Examples, but the scope of the present invention is not limited bythese.

Example 1 Syntheses of Methyl (R)-3-benzylamino-4-methylpentanoate and(S)-3-benzylamino-4-methylpentanoic Acid

To 2 mL of a 0.1 mol/L aqueous sodium phosphate solution with a pH of8.0 was added 100 mg of methyl (±)-3-benzylamino-4-methylpentanoate, andthe mixture was maintained at 30° C. To the resulting mixture was added1 mg of lipase (CAL; available from Roche, Chirazyme L-2 (trade name))originated from Candida antarctica at the same temperature, and themixture was reacted at 30° C. while stirring. After 45 minutes, at thetime when the conversion rate of the starting materials reached 49.9%, 2mol/L of hydrochloric acid was added to the reaction mixture to adjust apH to 1, then, the mixture was filtered through Celite (No. 545), andwashed with 5 ml of chloroform. To the resulting filtrate was added 20ml of chloroform whereby the product and the starting material wereextracted. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, and after filtration, the organic layer wasconcentrated under reduced pressure to obtain an oily substance. Theresulting oily substance was purified by silica gel columnchromatography (Wakogel C-200 (trade name), chloroform/methanol=98/2 to80/20 (volume ratio)) to obtain 42.0 mg (Isolated yield based onmethyl(±)-3-benzylamino-4-methylpentanoate=42.0%) ofmethyl(R)-3-benzylamino-4-methylpentanoate and 37.7 mg (Isolated yieldbased on methyl (±)-3-benzylamino-4-methylpentanoate=39.8%) of(S)-3-benzylamino-4-methylpentanoic acid.

When the optical purify of methyl (R)-3-benzylamino-4-methylpentanoatewas measured by using high performance liquid chromatography that usesan optically active column, it was 99.0% ee.

When the optical purify of (S)-3-benzylamino-4-methylpentanoic acid wasmeasured by using high performance liquid chromatography that uses anoptically active column, it was 99.2% ee.

Analytical conditions of high performance liquid chromatography;

Methyl 3-benzylamino-4-methylpentanoate

Column: chiral pack AS (0.46 cmΦ×25 cm, available from DAICEL CHEMICALINDUSTRIES, LTD.)

Solvent: hexane/isopropyl alcohol (=9/1 (volume ratio))

Flow rate: 0.5 ml/min

Temperature: 30° C.

3-Benzylamino-4-methylpentanoic Acid

Column: chiral CD-Ph (0.46 cmΦ×25 cm, available from SHISEIDO CO., LTD.)

Solvent: acetonitrile/water (=1/9 (volume ratio)) Potassium dihydrogenphosphate 40 mM pH 3.5

Flow rate: 0.5 ml/min

Temperature: 25° C.

Physical properties of the methyl (R)-3-benzylamino-4-methylpentanoatewere as follows.

¹H-NMR (δ (ppm), CDCl₃): 0.90 (d, 3H, J=6.8 Hz), 0.92 (d, 3H, J=6.8 Hz),1.88 (dqq, 1H, J=4.9, 6.8, 6.8 Hz), 2.34 (dd, 1H, J=8.3, 15.1 Hz), 2.45(dd, 1H, J=4.8, 15.1 Hz), 2.89 (ddd, 1H, J=4.8, 4.9, 8.3 Hz), 3.66 (s,3H), 3.77 (s, 2H), 7.20-7.34 (m, 5H)

¹³C-NMR (δ (ppm), CDCl₃): 17.5, 18.8, 21.3, 30.2, 35.5, 51.2, 51.7,59.3, 127.2, 128.4, 139.6, 173.4, 175.9

MS (CI, i-C₄H₁₀) m/z: 236 (MH⁺)

Elemental analysis; Calcd.: C, 71.45%; H, 9.00%; N, 5.95% Found: C,71.15%; H, 9.21%; N, 5.88%

Physical properties of the (S)-3-benzylamino-4-methylpentanoic acid wereas follows.

¹H-NMR (δ (ppm), CD₃OD): 0.93 (d, 3H, J=7.3 Hz), 0.95 (d, 3H, J=7.3 Hz),2.05 (dqq, 1H, J=4.9, 7.3, 7.3 Hz), 2.31 (dd, 1H, J=8.3, 16.6 Hz), 2.41(dd, 1H, J=3.9, 16.6 Hz), 2.88 (ddd, 1H, J=3.9, 4.9, 8.3 Hz), 4.04 (d,1H, J=13.7 Hz), 4.12 (d, 1H, J=13.7 Hz), 7.30-7.45 (m, 5H)

¹³C-NMR (δ (ppm), CD₃OD): 16.9, 19.7, 28.3, 31.7, 47.8, 58.8, 128.6,129.0, 129.3, 133.5, 176.0

MS (CI, i-C₄H₁₀) m/z: 222 (MH⁺)

Elemental analysis; Calcd.: C, 70.56%; H, 8.65%; N, 6.33% Found: C,69.28%; H, 8.72%; N, 6.21%

Incidentally, absolute configuration of an optically active methyl3-benzylamino-4-methylpentanoate was determined as follows. That is, 202mg of optically active methyl 3-benzylamino-4-methylpentanoate having anoptical purity of 99.9% ee or more obtained by the same procedures as inExample 1 was dissolved in 2 mL of methanol, 22.8 mg of 20%palladium/carbon powder was added to the solution, and the mixture wasreacted at room temperature while stirring. After 1 hour, the reactionmixture was filtered through Celite (No. 545), and washed with 5 ml ofmethanol. The resulting filtrate was concentrated under reduced pressureto obtain an oily substance. The resulting oily substance was purifiedby silica gel column chromatography (Wakogel C-200 (trade name),chloroform/methanol=98/2 to 0/100 (volume ratio)) to obtain 100 mg(Isolated yield based on optically active methyl3-benzylamino-4-methylpentanoate=90.0%) of optically active3-amino-4-methylpentanoic acid. Absolute configuration was determined bycomparing a specific rotatory power ([α]²³ _(D)+27.80 (C 0.20, MeOH)) ofthe resulting optically active 3-amino-4-methylpentanoic acid and a sign(literal value [α]²⁵ _(D)−28.2° (C 0.48, MeOH)) of a specific rotatorypower of (R)-3-amino-4-methylpentanoic acid described in Tetrahedron(Tetrahedron., 51 (45), 12237 (1995)).

Example 2 Syntheses of Methyl (R)-3-benzylamino-4-methylpentanoate and(S)-3-benzylamino-4-methylpentanoic Acid

To a mixed solvent of 1 mL of cyclohexane and 1 mL of water was added100 mg of methyl (±)-3-benzylamino-4-methylpentanoate, and the mixturewas maintained at 30° C. To the resulting mixture was added 1 mg oflipase (CAL; available from Roche, Chirazyme L-2 (trade name))originated from Candida antarctica at the same temperature, and themixture was reacted at 30° C. while stirring. After 100 minutes, at thetime when the conversion rate of the starting materials reached 50.0%, 2mol/L of hydrochloric acid was added to the reaction mixture to adjust apH to 1, filtered through Celite (No. 545), and washed with 5 ml ofchloroform. To the resulting filtrate was added 20 mol of chloroform,and the product and the starting materials were extracted. The organiclayer was washed with saturated brine, dried over anhydrous magnesiumsulfate, and after filtration, the organic layer was concentrated underreduced pressure to obtain an oily substance. The resulting oilysubstance was purified by silica gel column chromatography (WakogelC-200 (trade name), chloroform/methanol=98/2 to 80/20 (volume ratio)) toobtain 45.0 mg (Isolated yield based on methyl(±)-3-benzylamino-4-methylpentanoate=45.0%) of methyl(R)-3-benzylamino-4-methylpentanoate and 41.9 mg (Isolated yield basedon methyl (±)-3-benzylamino-4-methylpentanoate=44.6%) of(S)-3-benzylamino-4-methylpentanoic acid.

When the optical purify of methyl (R)-3-benzylamino-4-methylpentanoatewas measured by using high performance liquid chromatography that usesan optically active column, it was 99.0% ee or higher.

When the optical purify of (S)-3-benzylamino-4-methylpentanoic acid wasmeasured by using high performance liquid chromatography that uses anoptically active column, it was 99.9% ee or higher.

Analytical conditions of high performance liquid chromatography;

Methyl 3-benzylamino-4-methylpentanoate

Column: chiral pack AS (0.46 cmΦ×25 cm, available from DAICEL CHEMICALINDUSTRIES, LTD.)

Solvent: hexane/isopropyl alcohol (=9/1 (volume ratio))

Flow rate: 0.5 ml/min

Temperature: 30° C.

3-Benzylamino-4-methylpentanoic Acid

Column: chiral CD-Ph (0.46 cmΦ×25 cm, available from SHISEIDO CO., LTD.)

Solvent: acetonitrile/water (=1/9 (volume ratio)) Potassium dihydrogenphosphate 40 mM pH 3.5

Flow rate: 0.5 ml/min

Temperature: 25° C.

Incidentally, spectrum data were the same as those obtained in Example1.

Example 3 Syntheses of Methyl (R)-3-benzylamino-4-methylpentanoate and(S)-3-benzylamino-4-methylpentanoic Acid

To a mixed solvent of 5 mL of cyclohexane and 5 mL of water was added 1g of methyl(±)-3-benzylamino-4-methylpentanoate, and the mixture wasmaintained at 30° C. To the resulting mixture was added 1 mg of lipase(CAL; available from Roche, Chirazyme L-2 (trade name)) originated fromCandida antarctica at the same temperature, and the mixture was reactedat 30° C. while stirring. After 10 hours, at the time when theconversion rate of the starting materials reached 50.2%, 2 mol/L ofhydrochloric acid was added to the reaction mixture to adjust a pH to 1,filtered through Celite (No. 545), and washed with 10 ml of chloroform.To the resulting filtrate was added 20 mol of chloroform, and theproduct and the starting materials were extracted. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate, andafter filtration, the organic layer was concentrated under reducedpressure to obtain an oily substance. The resulting oily substance waspurified by silica gel column chromatography (Wakogel C-200 (tradename), chloroform/methanol=98/2 to 80/20 (volume ratio)) to obtain 492mg (Isolated yield based on methyl(±)-3-benzylamino-4-methylpentanoate=49.2%) of methyl(R)-3-benzylamino-4-methylpentanoate and 443 mg (Isolated yield based onmethyl (±)-3-benzylamino-4-methylpentanoate=47.1%) of(S)-3-benzylamino-4-methylpentanoic acid.

When the optical purify of methyl (R)-3-benzylamino-4-methylpentanoatewas measured by using high performance liquid chromatography that usesan optically active column, it was 99.1% ee.

When the optical purify of (S)-3-benzylamino-4-methylpentanoic acid wasmeasured by using high performance liquid chromatography that uses anoptically active column, it was 98.4% ee.

Analytical conditions of high performance liquid chromatography;

Methyl 3-benzylamino-4-methylpentanoate

Column: chiral pack AS (0.46 cmΦ×25 cm, available from DAICEL CHEMICALINDUSTRIES, LTD.)

Solvent: hexane/isopropyl alcohol (=9/1 (volume ratio))

Flow rate: 0.5 ml/min

Temperature: 30° C.

3-Benzylamino-4-methylpentanoic Acid

Column: chiral CD-Ph (0.46 cmΦ×25 cm, available from SHISEIDO CO., LTD.)

Solvent: acetonitrile/water (=1/9 (volume ratio)) Potassium dihydrogenphosphate 40 mM pH 3.5

Flow rate: 0.5 ml/min

Temperature: 25° C.

Incidentally, spectrum data were the same as those obtained in Example1.

Example 4 Syntheses of Methyl (S)-3-benzylaminopentanoate and(R)-3-benzylaminopentanoic Acid

To 2 mL of a 0.1 mol/L aqueous sodium phosphate solution with a pH of8.0 was added 100 mg of methyl (±)-3-benzylaminopentanoate, and themixture was maintained at 30° C. To the resulting mixture was added 1 mgof lipase (CAL; available from Roche, Chirazyme L-2 (trade name))originated from Candida antarctica at the same temperature, and themixture was reacted at 30° C. while stirring. After 10 minutes, at thetime when the conversion rate of the starting materials reached 47.5%, 2mol/L of hydrochloric acid was added to the reaction mixture to adjust apH to 1, filtered through Celite (No. 545), and washed with 5 ml ofchloroform. To the resulting filtrate was added 20 mol of chloroform,and the product and the starting materials were extracted. The organiclayer was washed with saturated brine, dried over anhydrous magnesiumsulfate, and after filtration, the organic layer was concentrated underreduced pressure to obtain an oily substance. The resulting oilysubstance was purified by silica gel column chromatography (WakogelC-200 (trade name), chloroform/methanol=98/2 to 80/20 (volume ratio)) toobtain 45.4 mg (Isolated yield based on methyl(±)-3-benzylaminopentanoate=45.4%) of methyl (S)-3-benzylaminopentanoateand 39.8 mg (Isolated yield based on methyl(±)-3-benzylaminopentanoate=42.5%) of (R)-3-benzylaminopentanoic acid.

When the optical purify of methyl (S)-3-benzylaminopentanoate wasmeasured by using high performance liquid chromatography that uses anoptically active column, it was 87.6% ee.

When the optical purify of (R)-3-benzylaminopentanoic acid was measuredby using high performance liquid chromatography that uses an opticallyactive column, it was 96.8% ee.

Analytical conditions of high performance liquid chromatography;

Methyl 3-benzylaminopentanoate

Column: chiral pack AS (0.46 cmΦ25 cm, available from DAICEL CHEMICALINDUSTRIES, LTD.)

Solvent: hexane/isopropyl alcohol (=9/1 (volume ratio))

Flow rate: 0.5 ml/min

Temperature: 30° C.

3-Benzylaminopentanoic Acid

Column: chiral CD-Ph (0.46 cmΦ×25 cm, available from SHISEIDO CO., LTD.)

Solvent: acetonitrile/water (=1/9 (volume ratio)) Potassium dihydrogenphosphate 40 mM pH 3.5

Flow rate: 0.5 ml/min

Temperature: 25° C.

Physical properties of the methyl (S)-3-benzylaminopentanoate were asfollows.

¹H-NMR (δ (ppm), CDCl₃): 0.92 (t, 3H, J=7.3 Hz), 1.53 (dq, 2H, J=5.9,7.3 Hz), 2.44 (dd, 1H, J=6.8, 15.1 Hz), 2.48 (dd, 1H, J=5.4, 15.1 Hz),2.97 (ddt, 1H, J=5.4, 6.8, 5.9 Hz), 3.67 (s, 3H), 3.78 (s, 2H),7.21-7.34 (m, 5H)

¹³C-NMR (δ (ppm), CDCl₃): 9.9, 26.9, 38.7, 51.0, 51.5, 55.5, 126.9,128.1, 128.4, 129.0, 140.6, 173.1

MS (CI, i-C₄H₁₀) m/z: 222 (MH⁺)

Elemental analysis; Calcd.: C, 70.56%; H, 8.65%; N, 6.33% Found: C,70.04%; H, 8.74%; N, 6.34%

Physical properties of the (R)-3-benzylaminopentanoic acid were asfollows.

¹H-NMR (δ (ppm), CD₃OD): 1.02 (dd, 3H, J=7.3, 7.3 Hz), 1.64 (ddq, 1H,J=7.3, 8.3, 14.7 Hz), 1.92 (ddq, 1H, J=4.4, 7.3, 14.7 Hz), 2.36 (dd, 1H,J=8.8, 17.1 Hz), 2.63 (dd, 1H, J=3.9, 17.1), 3.30 (dddd, 1H, J=3.9, 4.4,8.3, 8.8 Hz), 4.18 (d, 1H, J=13.2 Hz), 4.24 (d, 1H, J=13.2), 7.40-7.51(m, 5H)

¹³C-NMR (δ (ppm), CD₃OD): 10.2, 25.0, 35.7, 58.7, 130.4, 130.5, 130.6,133.6, 178.1

MS (CI, i-C₄H₁₀) m/z: 208 (MH⁺)

Example 5 Syntheses of Methyl (S)-3-benzylaminopentanoate and(R)-3-benzylaminopentanoic Acid

To a mixed solvent of 1 mL of cyclohexane and 1 mL of water was added100 mg of methyl (±)-3-benzylaminopentanoate, and the mixture wasmaintained at 30° C. To the resulting mixture was added 1 mg of lipase(CAL; available from Roche, Chirazyme L-2 (trade name)) originated fromCandida antarctica at the same temperature, and the mixture was reactedat 30° C. while stirring. After 30 minutes, at the time when theconversion rate of the starting materials reached 50.6%, 2 mol/L ofhydrochloric acid was added to the reaction mixture to adjust a pH to 1,filtered through Celite (No. 545), and washed with 5 ml of chloroform.To the resulting filtrate was added 20 mol of chloroform, and theproduct and the starting materials were extracted. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate, andafter filtration, the organic layer was concentrated under reducedpressure to obtain an oily substance. The resulting oily substance waspurified by silica gel column chromatography (Wakogel C-200 (tradename), chloroform/methanol=98/2 to 80/20 (volume ratio)) to obtain 46.2mg (Isolated yield based on methyl (±)-3-benzylaminopentanoate=46.2%) ofmethyl (S)-3-benzylaminopentanoate and 40.3 mg (Isolated yield based onmethyl (±)-3-benzylaminopentanoate=43.0%) of (R)-3-benzylaminopentanoicacid.

When the optical purify of methyl (S)-3-benzylaminopentanoate wasmeasured by using high performance liquid chromatography that uses anoptically active column, it was 98.1% ee.

When the optical purify of (R)-3-benzylaminopentanoic acid was measuredby using high performance liquid chromatography that uses an opticallyactive column, it was 95.0% ee.

Analytical conditions of high performance liquid chromatography;

Methyl 3-benzylaminopentanoate

Column: chiral pack AS (0.46 cmΦ×25 cm, available from DAICEL CHEMICALINDUSTRIES, LTD.)

Solvent: hexane/isopropyl alcohol (=9/1 (volume ratio))

Flow rate: 0.5 ml/min

Temperature: 30° C.

3-Benzylaminopentanoic Acid

Column: chiral CD-Ph (0.46 cmΦ×25 cm, available from SHISEIDO CO., LTD.)

Solvent: acetonitrile/water (=1/9 (volume ratio)) Potassium dihydrogenphosphate 40 mM pH 3.5

Flow rate: 0.5 ml/min

Temperature: 25° C.

Incidentally, spectrum data were the same as those obtained in Example3.

Example 6 Syntheses of Methyl (S)-3-benzylaminobutyrate and(R)-3-benzylaminobutyric Acid

To a mixed solvent of 1 mL of cyclohexane and 1 mL of water was added100 mg of methyl (±)-3-benzylaminobutyrate, and the mixture wasmaintained at 30° C. To the resulting mixture was added 0.1 mg of lipase(CAL; available from Roche, Chirazyme L-2 (trade name)) originated fromCandida antarctica at the same temperature, and the mixture was reactedat 30° C. while stirring. After 4.5 hours, at the time when theconversion rate of the starting materials reached 52.6%, 2 mol/L ofhydrochloric acid was added to the reaction mixture to adjust a pH to 1,and 20 ml of chloroform was added to the mixture to extract the startingmaterials. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, and after filtration, the organic layer wasconcentrated under reduced pressure to obtain an oily substance. Theresulting oily substance was purified by silica gel columnchromatography (Wakogel C-200 (trade name), chloroform/methanol=98/2 to80/20 (volume ratio)) to obtain 42.8 mg (Isolated yield based on methyl(±)-3-benzylaminobutyrate=42.8%) of methyl (S)-3-benzylaminobutyrate. Onthe other hand, the aqueous layer which contains the product wasconcentrated under reduced pressure to obtain an oily substance. Theresulting oily substance was purified by silica gel columnchromatography (Wakogel C-200 (trade name), chloroform/methanol=80/20(volume ratio)) to obtain 40.0 mg (Isolated yield based on methyl(±)-3-benzylaminobutyrate=43.0%) of (R)-3-benzylaminobutyric acid.

When the optical purify of methyl (S)-3-benzylaminobutyrate was measuredby using high performance liquid chromatography that uses an opticallyactive column, it was 95.2% ee.

(R)-3-benzylaminobutyric acid was introduced into a methyl ester andwhen the optical purity of the resulting compound was measured by usinghigh performance liquid chromatography that uses an optically activecolumn, it was 85.9% ee.

Analytical conditions of high performance liquid chromatography;

Methyl 3-benzylaminobutyrate

Column: chiral pack AS (0.46 cmΦ×25 cm, available from DAICEL CHEMICALINDUSTRIES, LTD.)

Solvent: hexane/isopropyl alcohol (=9/1 (volume ratio))

Flow rate: 0.5 ml/min

Temperature: 30° C.

Physical properties of the methyl (S)-3-benzylaminobutyrate were asfollows.

¹H-NMR (δ (ppm), CDCl₃): 1.42 (d, 1H, J=6.8 Hz), 2.75 (dd, 1H, J=7.3,17.1 Hz), 2.88 (dd, 1H, J=5.9, 17.1 Hz), 3.65 (ddd, 1H, J=5.9, 6.8, 7.3Hz), 3.73 (s, 3H), 4.21 (d, 1H, J=14.6 Hz), 4.27 (d, 1H, J=14.6 Hz),7.41-7.53 (m, 5H)

¹³C-NMR (δ (ppm), CDCl₃): 20.5, 41.4, 49.7, 51.2, 51.5, 126.9, 128.1,128.4, 140.4, 172.8

MS (CI, i-C₄H₁₀) m/z: 208 (MH⁺)

Elemental analysis; Calcd.: C, 69.38%; H, 8.25%; N, 6.74% Found: C,68.74%; H, 8.23%; N, 6.76%

Physical properties of the (R)-3-benzylaminobutyric acid were asfollows.

¹H-NMR (δ (ppm), CD₃OD): 1.37 (d, 3H, J=6.4 Hz), 2.37 (dd, 1H, J=8.8,17.1 Hz), 2.55 (dd, 1H, J=4.4, 17.1 Hz), 3.47 (ddd, 1H, J=4.4, 6.4, 8.8Hz), 4.16 (d, 1H, J=13.2 Hz), 4.25 (d, 1H, J=13.2 Hz)

¹³C-NMR (δ (ppm), CD₃OD): 17.1, 39.4, 53.3, 130.4, 130.5, 133.5, 177.9

MS (CI, i-C₄H₁₀) m/z: 194 (MH⁺)

Elemental analysis; Calcd.: C, 68.37%; H, 7.82%; N, 7.25% Found: C,67.21%; H, 7.84%; N, 7.07%

Example 7 Syntheses of Methyl (R)-3-benzylamino-3-phenylpropionate and(S)-3-benzylamino-3-phenylpropionic Acid

To 10 mL of 0.1 mol/L aqueous sodium phosphate solution with a pH of 8.0was added 1.00 g of methyl (±)-3-benzylamino-3-phenylpropionate, and themixture was maintained at 30° C. To the resulting mixture was added 10mg of lipase (CAL; available from Roche, Chirazyme L-2 (trade name))originated from Candida antarctica at the same temperature, and themixture was reacted at 30° C. while stirring. After 23 hours, at thetime when the conversion rate of the starting materials reached 49.6%, 2mol/L of hydrochloric acid was added to the reaction mixture to adjust apH to 1, filtered through Celite (No. 545), and washed with 10 ml ofchloroform 10 ml. To the resulting filtrate was added 20 mol ofchloroform, and the product and the starting materials were extracted.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and after filtration, the organic layer wasconcentrated under reduced pressure to obtain an oily substance. Theresulting oily substance was purified by silica gel columnchromatography (Wakogel C-200 (trade name), chloroform/methanol=98/2 to80/20 (volume ratio)) to obtain 438 mg (Isolated yield based on methyl(±)-3-benzylamino-3-phenylpropionate=43.8%) of methyl(R)-3-benzylamino-3-phenylpropionate and 410 mg (Isolated yield based onmethyl (±)-3-benzylamino-3-phenylpropionate=43.2%) of(S)-3-benzylamino-3-phenylpropionic acid.

When the optical purify of methyl (R)-3-benzylamino-3-phenylpropionatewas measured by using high performance liquid chromatography that usesan optically active column, it was 94.2% ee.

When the optical purify of (S)-3-benzylamino-3-phenylpropionic acid wasmeasured by using high performance liquid chromatography that uses anoptically active column, it was 95.9% ee.

Analytical conditions of high performance liquid chromatography;

Methyl 3-benzylamino-3-phenylpropionate

Column: chiral pack AS (0.46 cmΦ×25 cm, available from DAICEL CHEMICALINDUSTRIES, LTD.)

Solvent: hexane/isopropyl alcohol (=9/1 (volume ratio))

Flow rate: 0.5 ml/min

Temperature: 30° C.

3-Benzylamino-3-phenylpropionic Acid

Column: chiral CD-Ph (0.46 cmΦ×25 cm, available from SHISEIDO CO., LTD.)

Solvent: acetonitrile/water (=1/9 (volume ratio)) Potassium dihydrogenphosphate 40 mM pH 3.5

Flow rate: 0.5 ml/min

Temperature: 25° C.

Physical properties of the methyl (R)-3-benzylamino-3-phenylpropionatewere as follows.

¹H-NMR (δ (ppm), CDCl₃): 2.62 (dd, 1H, J=5.4, 15.6 Hz), 2.72 (dd, 1H,J=8.8, 15.6 Hz), 3.53 (d, 1H, J=13.2 Hz), 3.62 (s, 3H), 3.65 (d, 1H,J=13.2 Hz), 4.11 (dd, 1H, J=5.4, 8.8 Hz), 7.21-7.35 (m, 10H)

¹³C-NMR (δ (ppm), CDCl₃): 42.9, 51.3, 51.6, 58.8, 126.9, 127.1, 127.5,128.1, 128.3, 128.6, 140.3, 142.5, 172.2

MS (CI, i-C₄H₁₀) m/z: 270 (MH⁺)

Physical properties of the (S)-3-benzylamino-3-phenylpropionic acid wereas follows.

¹H-NMR (δ (ppm), CD₃OD): 2.65 (dd, 1H, J=4.4, 17.1 Hz), 2.84 (dd, 1H,J=10.3, 17.1 Hz), 3.96 (d, 1H, J=13.2 Hz), 4.02 (d, 1H, J=13.2 Hz), 4.48(dd, 1H, J=4.4, 10.3 Hz), 7.36-7.51 (m, 10H)

¹³C-NMR (δ (ppm), CD₃OD): 40.1, 49.8, 61.2, 129.1, 130.3, 130.4, 130.5,130.7, 133.3, 136.4, 177.3

MS (CI, i-C₄H₁₀) m/z: 256 (MH⁺)

Example 8 Syntheses of Methyl (R)-3-benzylamino-3-phenylpropionate and(S)-3-benzylamino-3-phenylpropionic Acid

To a mixed solvent of 1 mL of cyclohexane and 1 mL of water was added100 mg of methyl (±)-3-benzylamino-3-phenylpropionate and the mixturewas maintained at 30° C. To the resulting mixture was added 5 mg oflipase (CAL; available from Roche, Chirazyme L-2 (trade name))originated from Candida antarctica at the same temperature, and themixture was reacted at 30° C. while stirring. After 31 hours, at thetime when the conversion rate of the starting materials reached 48.9%, 2mol/L of hydrochloric acid was added to the reaction mixture to adjust apH to 1, filtered through Celite (No. 545), and washed with 5 ml ofchloroform. To the resulting filtrate was added 20 mol of chloroform,and the product and the starting materials were extracted. The organiclayer was washed with saturated brine, dried over anhydrous magnesiumsulfate, and after filtration, the organic layer was concentrated underreduced pressure to obtain an oily substance. The resulting oilysubstance was purified by silica gel column chromatography (WakogelC-200 (trade name), chloroform/methanol=98/2 to 80/20 (volume ratio)) toobtain 41.6 mg (Isolated yield based on methyl(±)-3-benzylamino-3-phenylpropionate=41.6%) of methyl(R)-3-benzylamino-3-phenylpropionate and 40.2 mg (Isolated yield basedon methyl (±)-3-benzylamino-3-phenylpropionate=42.4%) of(S)-3-benzylamino-3-phenylpropionic acid.

When the optical purify of methyl (R)-3-benzylamino-3-phenylpropionatewas measured by using high performance liquid chromatography that usesan optically active column, it was 93.5% ee.

When the optical purify of (S)-3-benzylamino-3-phenylpropionic acid wasmeasured by using high performance liquid chromatography that uses anoptically active column, it was 97.9% ee.

Analytical conditions of high performance liquid chromatography;

Methyl 3-benzylamino-3-phenylpropionate

Column: chiral pack AS (0.46 cmΦ×25 cm, available from DAICEL CHEMICALINDUSTRIES, LTD.)

Solvent: hexane/isopropyl alcohol (=9/1 (volume ratio))

Flow rate: 0.5 ml/min

Temperature: 30° C.

3-Benzylamino-3-phenylpropionic Acid

Column: chiral CD-Ph (0.46 cmΦ×25 cm, available from SHISEIDO CO., LTD.)

Solvent: acetonitrile/water (=1/9 (volume ratio)) Potassium dihydrogenphosphate 40 mM pH 3.5

Flow rate: 0.5 ml/min

Temperature: 25° C.

Incidentally, spectrum data were the same as those obtained in Example7.

Example 9 Syntheses of Methyl(R)-3-benzylamino-3-(4-fluorophenyl)propionate and(S)-3-benzylamino-3-(4-fluorophenyl)propionic Acid

To 2 mL of a 0.1 mol/L aqueous sodium phosphate solution with a pH of8.0 was added 100 mg of methyl(±)-3-benzylamino-3-(4-fluorophenyl)propionate and the mixture wasmaintained at 30° C. To the resulting mixture was added 5 mg of lipase(CAL; available from Roche, Chirazyme L-2 (trade name)) originated fromCandida antarctica at the same temperature, and the mixture was reactedat 30° C. while stirring. After 4.5 hours, at the time when theconversion rate of the starting materials reached 50.4%, 2 mol/L ofhydrochloric acid was added to the reaction mixture to adjust a pH to 1,filtered through Celite (No. 545), and washed with 5 ml of chloroform.To the resulting filtrate was added 20 mol of chloroform, and theproduct and the starting materials were extracted. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate, andafter filtration, the organic layer was concentrated under reducedpressure to obtain an oily substance. The resulting oily substance waspurified by silica gel column chromatography (Wakogel C-200 (tradename), chloroform/methanol=98/2 to 80/20 (volume ratio)) to obtain 40.2mg (Isolated yield based on methyl(±)-3-benzyamino-3-(4-fluorophenyl)propionate=40.2%) of methyl(R)-3-benzylamino-3-(4-fluorophenyl)propionate and 39.9 mg (Isolatedyield based on methyl(±)-3-benzylamino-3-(4-fluorophenyl)propionate=42.0%) of(S)-3-benzylamino-3-(4-fluorophenyl)propionic acid.

When the optical purify of methyl(R)-3-benzylamino-3-(4-fluorophenyl)propionate was measured by usinghigh performance liquid chromatography that uses an optically activecolumn, it was 91.8% ee.

When the optical purify of (S)-3-benzylamino-3-(4-fluorophenyl)propionicacid was measured by using high performance liquid chromatography thatuses an optically active column, it was 90.3% ee.

Analytical conditions of high performance liquid chromatography;

Methyl 3-benzylamino-3-(4-fluorophenyl)propionate

Column: chiral pack AS (0.46 cmΦ×25 cm, available from DAICEL CHEMICALINDUSTRIES, LTD.)

Solvent: hexane/isopropyl alcohol (=9/1 (volume ratio))

Flow rate: 0.5 ml/min

Temperature: 30° C.

3-Benzylamino-3-(4-fluorophenyl)propionic Acid

Column: chiral CD-Ph (0.46 cmΦ×25 cm, available from SHISEIDO CO., LTD.)

Solvent: acetonitrile/water (=1/9 (volume ratio)) Potassium dihydrogenphosphate 40 mM pH 3.5

Flow rate: 0.5 ml/min

Temperature: 25° C.

Physical properties of the methyl(R)-3-benzylamino-3-(4-fluorophenyl)propionate are as follows.

¹H-NMR (δ (ppm), CDCl₃): 2.59 (dd, 1H, J=5.4, 15.6 Hz), 2.70 (dd, 1H,J=8.8, 15.6 Hz), 3.52 (d, 1H, J=13.2 Hz), 3.63 (s, 3H), 3.65 (d, 1H,J=13.2 Hz), 4.10 (dd, 1H, J=5.4, 8.8 Hz), 7.0-7.1 (m, 4H), 7.2-7.3 (m,5H)

¹³C-NMR (δ (ppm), CDCl₃): 42.9, 51.3, 51.6, 58.1, 60.4, 115.3, 115.5,127.0, 128.1, 128.2, 128.3, 128.4, 128.6, 128.7, 138.2, 140.1, 160.9,163.4, 172.0

MS (CI, i-C₄H₁₀) m/z: 288 (MH⁺)

Elemental analysis; Calcd.: C, 71.06%; H, 6.31%; N, 4.87% Found: C,70.69%; H, 6.42%; N, 4.86%

Physical properties of the (S)-3-benzylamino-3-(4-fluorophenyl)propionicacid were as follows.

¹H-NMR (δ (ppm), CD₃OD): 2.65 (dd, 1H, J=4.4, 17.1 Hz), 2.82 (dd, 1H,J=10.3, 17.1 Hz), 3.95 (d, 1H, J=13.2 Hz), 4.02 (d, 1H, J=13.2 Hz), 4.50(dd, 1H, J=4.4, 10.3 Hz), 7.19-7.25 (m, 2H), 7.36-7.45 (m, 4H),7.49-7.52 (m, 2H)

¹³C-NMR (δ (ppm), CD₃OD): 40.2, 60.5, 117.2, 117.4, 130.3, 130.4, 130.5,131.3, 131.4, 132.8, 133.6, 163.5, 165.9, 177.2

MS (CI, i-C₄H₁₀) m/z: 274 (MH⁺)

Elemental analysis; Calcd.: C, 70.31%; H, 5.90%; N, 5.12% Found: C,69.44%; H, 6.08%; N, 5.04%

Example 10 Syntheses of Methyl(R)-3-benzylamino-3-(4-fluorophenyl)propionate and(S)-3-benzylamino-3-(4-fluorophenyl)propionic Acid

To a mixed solvent of 1 mL of cyclohexane and 1 mL of water was added100 mg of methyl (±)-3-benzylamino-3-(4-fluorophenyl)propionate, and themixture was maintained at 30° C. To the resulting mixture was added 5 mgof lipase (CAL; available from Roche, Chirazyme L-2 (trade name))originated from Candida antarctica at the same temperature, and themixture was reacted at 30° C. while stirring. After 58 hours, at thetime when the conversion rate of the starting materials reached 48.0%, 2mol/L of hydrochloric acid was added to the reaction mixture to adjust apH to 1, filtered through Celite (No. 545), and washed with 5 ml ofchloroform. To the resulting filtrate was added 20 mol of chloroform,and the product and the starting materials were extracted. The organiclayer was washed with saturated brine, dried over anhydrous magnesiumsulfate, and after filtration, the organic layer was concentrated underreduced pressure to obtain an oily substance. The resulting oilysubstance was purified by silica gel column chromatography (WakogelC-200 (trade name), chloroform/methanol=98/2 to 80/20 (volume ratio)) toobtain 41.0 mg (Isolated yield based on methyl(±)-3-benzylamino-3-(4-fluorophenyl)propionate=41.0%) of methyl(R)-3-benzylamino-3-(4-fluorophenyl)propionate and 36.6 mg (Isolatedyield based on methyl(±)-3-benzylamino-3-(4-fluorophenyl)propionate=38.5%) of(S)-3-benzylamino-3-(4-fluorophenyl)propionic acid.

When the optical purify of methyl(R)-3-benzylamino-3-(4-fluorophenyl)propionate was measured by usinghigh performance liquid chromatography that uses an optically activecolumn, it was 86.5% ee.

When the optical purify of (S)-3-benzylamino-3-(4-fluorophenyl)propionicacid was measured by using high performance liquid chromatography thatuses an optically active column, it was 93.8% ee.

Analytical conditions of high performance liquid chromatography;

Methyl 3-benzylamino-3-(4-fluorophenyl)propionate

Column: chiral pack AS (0.46 cmΦ×25 cm, available from DAICEL CHEMICALINDUSTRIES, LTD.)

Solvent: hexane/isopropyl alcohol (=9/1 (volume ratio))

Flow rate: 0.5 ml/min

Temperature: 30° C.

3-Benzylamino-3-(4-fluorophenyl)propionic Acid

Column: chiral CD-Ph (0.46 cmΦ×25 cm, available from SHISEIDO CO., LTD.)

Solvent: acetonitrile/water (=1/9 (volume ratio)) Potassium dihydrogenphosphate 40 mM pH 3.5

Flow rate: 0.5 ml/min

Temperature: 25° C.

Incidentally, spectrum data were the same as those obtained in Example9.

Example 11 Synthesis of Optically Active3-(3-benzylamino)-3-(3,4-methylenedioxyphenyl)propionic Acid

To 4 mL of water were added 400 mg (1.28 mmol) of methyl(±)-3-benzylamino-3-(3,4-methylenedioxyphenyl)propionate and 107 mg(1.28 mmol) of sodium hydrogen carbonate, and the mixture was maintainedto 30° C. To the resulting mixture was added 2 mg of lipase (CAL;available from Roche, Chirazyme L-2 (trade name)) originated fromCandida antarctica at the same temperature, and the mixture was reactedat 30° C. while stirring. After 20 hours, at the time when theconversion rate of the starting materials reached 46.2%, 8 ml of ethylacetate and 112 mg of sodium hydrogen carbonate were added to thereaction mixture and the aqueous layer was extracted. The resultingaqueous layer was adjusted to an inner pH of 2.0 with 2 mol/L ofhydrochloric acid aqueous solution, and 8 ml of ethyl acetate and 500 mgof sodium chloride were added to the mixture to extract the organiclayer. The resulting organic layer was dried over magnesium sulfate,filtered and concentrated to obtain 135 mg (Isolated yield based onmethyl (±)-3-benzylamino-3-(4-fluorophenyl)propionate=35.3%) of (R) or(S)-3-benzylamino-3-(3,4-methylenedioxyphenyl)propionic acid as whitecrystal.

When the optical purify of 3-(R) or(S)-benzylamino-3-(3,4-methylenedioxyphenyl)propionic acid was measuredby using high performance liquid chromatography that uses an opticallyactive column, it was 97.7% ee.

Analytical conditions of high performance liquid chromatography;

3-(R) or (S)-benzylamino-3-(3,4-methylenedioxyphenyl)propionic Acid

Column: chiral CD-Ph (0.46 cmΦ×25 cm, available from SHISEIDO CO., LTD.)

Solvent: acetonitrile/water (=1/9 (volume ratio)) Potassium dihydrogenphosphate 40 mM pH 3.5

Flow rate: 0.5 ml/min

Temperature: 25° C.

Physical properties of the 3-(R) or(S)-benzylamino-3-(3,4-methylenedioxyphenyl)propionic acid are asfollows.

¹H-NMR (δ (ppm), CD₃OD): 2.61 (dd, 1H, J=4.4, 17.1 Hz), 2.80 (dd, 1H,J=10.3, 17.1 Hz), 3.95 (d, 1H, J=13.2 Hz), 3.99 (d, 1H, J=13.2 Hz), 4.38(dd, 1H, J=4.4, 10.3 Hz), 4.91 (brs, 1H), 6.00 (d, 1H, J=1.5 Hz),7.37-7.42 (m, 3H), 7.37-7.42 (m, 5H)

¹³C-NMR (δ (ppm), CD₃OD): 40.4, 61.1, 103.0, 108.8, 109.8, 123.5, 130.1,130.3, 130.5, 133.7, 150.1, 177.5

MS (CI, i-C₄H₁₀) m/z: 300 (MH⁺)

Example 12 Synthesis of Optically Active3-(3-benzylamino)-3-(3,4-methylenedioxyphenyl)propionic Acid

To 37 mL of water were added 7.49 g (23.9 mmol) of methyl(±)-3-benzylamino-3-(3,4-methylenedioxyphenyl)propionate and 1.00 g(12.0 mmol) of sodium hydrogen carbonate, and the mixture was maintainedat 30° C. To the resulting mixture was added 37.5 mg of lipase (CAL;available from Roche, Chirazyme L-2 (trade name)) originated fromCandida antarctica at the same temperature, and the mixture was reactedat 30° C. while stirring. After 24 hours, at the time when theconversion rate of the starting materials reached 29.1%, 40 ml oftoluene was added to the reaction mixture. After the resulting mixturewas stirred for 15 minutes at room temperature, the mixture was filteredand dried to obtain 1.52 g (Isolated yield based on methyl(±)-3-benzylamino-3-(4-fluorophenyl)propionate=21.2%) of 3-(R) or(S)-benzylamino-3-(3,4-methylenedioxyphenyl)propionic acid as whitecrystal.

When the optical purify of 3-(R) or(S)-benzylamino-3-(3,4-methylenedioxyphenyl)propionic acid was measuredby using high performance liquid chromatography that uses an opticallyactive column, it was 99.3% ee.

Incidentally, spectrum data were the same as those obtained in Example1.

Example 13 Synthesis of Optically Active3-(3-benzylamino)-3-(p-tolyl)propionic Acid

To 372 mL of water were added 37.20 g (0.13 mol) of methyl(±)-3-benzylamino-3-(p-tolyl)propionate and 11.03 g (0.13 mol) of sodiumhydrogen carbonate, and the mixture was maintained at 30° C. To theresulting mixture was added 186 mg of lipase (CAL; available from Roche,Chirazyme L-2 (trade name)) originated from Candida antarctica at thesame temperature, and the mixture was reacted at 30° C. while stirring.After 8.5 hours, at the time when the conversion rate of the startingmaterials reached 39.4%, the reaction mixture was filtered to obtain asolid state product. To the resulting product was added 200 ml oftoluene and the mixture was stirred at room temperature for 2 hours,then, filtered and dried to obtain 11.11 g (Isolated yield based onmethyl (±)-3-benzylamino-3-(4-fluorophenyl)propionate=31.4%) of 3-(R) or(S)-benzylamino-3-(p-tolyl)propionic acid as white crystal.

When the optical purify of 3-(R) or (S)-benzylamino-3-(p-tolyl)propionicacid was measured by using high performance liquid chromatography thatuses an optically active column, it was 99.3% ee.

Analytical conditions of high performance liquid chromatography;

3-(R) or (S)-benzylamino-3-(p-tolyl)propionic Acid

Column: chiral CD-Ph (0.46 cmΦ×25 cm, available from SHISEIDO CO., LTD.)

Solvent: acetonitrile/water (=1/9 (volume ratio)) Potassium dihydrogenphosphate 40 mM pH 3.5

Flow rate: 0.5 ml/min

Temperature: 25° C.

Physical properties of the 3-(R) or (S)-benzylamino-3-(p-tolyl)propionicacid were as follows.

¹H-NMR (δ (ppm), CD₃OD): 2.38 (s, 3H), 2.62 (dd, 1H, J=4.4, 16.6 Hz),2.83 (dd, 1H, J=10.3, 16.6 Hz), 3.94 (d, 1H, J=13.2 Hz), 3.99 (d, 1H,J=13.2 Hz), 4.43 (dd, 1H, J=4.4, 10.3 Hz), 4.93 (brs, 1H), 7.28-7.43 (m,9H)

¹³C-NMR (δ (ppm), CD₃OD): 21.2, 40.2, 61.0, 129.1, 130.3, 130.4, 130.5,131.1, 133.3, 133.4, 140.9, 177.5

MS (CI, i-C₄H₁₀) m/z: 270 (MH⁺)

Elemental analysis; Calcd.: C, 75.80%; H, 7.12%; N, 5.20% Found: C,75.32%; H, 7.27%; N, 5.27%

Example 14 Syntheses of Methyl (S)-N-benzylhomopipecolate and(R)-N-benzylhomopipecolic Acid

To 1 mL of 0.1 mol/L aqueous sodium phosphate solution with a pH of 8.0was added 50.0 mg of methyl (±)-N-benzylhomopipecolate, and the mixturewas maintained at 30° C. To the resulting mixture was added 2 mg oflipase (CAL; available from Roche, Chirazyme L-2 (trade name))originated from Candida antarctica at the same temperature, and themixture was reacted at 30° C. while stirring. After 110 minutes, at thetime when the conversion rate of the starting materials reached 41.6%, 2mol/L of hydrochloric acid was added to the reaction mixture to adjust apH to 1, filtered through Celite (No. 545), and washed with 5 ml ofmethanol. To the resulting filtrate was added 20 mol of chloroform, andthe product and the starting materials were extracted. The organic layerwas washed with saturated brine, dried over anhydrous magnesium sulfate,and after filtration, the organic layer was concentrated under reducedpressure to obtain an oily substance. The resulting oily substance waspurified by silica gel column chromatography (Wakogel C-200 (tradename), chloroform/methanol=98/2 to 80/20 (volume ratio)) to obtain 18.6mg (Isolated yield based on methyl (±)-N-benzylhomopipecolate=37.2%) ofmethyl (S)-N-benzylhomopipecolate and 21.7 mg (Isolated yield based onmethyl (±)-N-benzylhomopipecolate=45.2%) of (R)-N-benzylhomopipecolicacid.

When the optical purify of methyl (S)-N-benzylhomopipecolate wasmeasured by using high performance liquid chromatography that uses anoptically active column, it was 68.0% ee.

When the optical purify of (R)-N-benzylhomopipecolic acid was measuredby using high performance liquid chromatography that uses an opticallyactive column, it was 95.4% ee.

Analytical conditions of high performance liquid chromatography;

Methyl N-benzylhomopipecolate

Column: chiral pack AS (0.46 cmΦ×25 cm, available from DAICEL CHEMICALINDUSTRIES, LTD.)

Solvent: hexane/isopropyl alcohol (=9/1 (volume ratio))

Flow rate: 0.5 ml/min

Temperature: 30° C.

N-benzylhomopipecolic Acid

Column: chiral CD-Ph (0.46 cmΦ×25 cm, available from SHISEIDO CO., LTD.)

Solvent: acetonitrile/water (=1/9 (volume ratio)) Potassium dihydrogenphosphate 40 mM pH 3.5

Flow rate: 0.5 ml/min

Temperature: 25° C.

Physical properties of the methyl (S)-N-benzylhomopipecolate were asfollows.

¹H-NMR (δ (ppm), CDCl₃): 1.38-1.64 (m, 6H), 2.18 (ddd, 1H, J=3.9, 7.8,16.1 Hz), 2.45 (dd, 1H, J=7.8, 14.7 Hz), 2.62 (ddd, 1H, J=2.9, 3.9, 16.1Hz), 2.72 (dd, 1H, J=4.9, 14.7 Hz), 2.97 (dddd, 1H, J=4.4, 4.9, 7.8, 7.8Hz), 3.35 (d, 1H, J=13.7 Hz), 3.67 (s, 3H), 3.80 (d, 1H, J=13.7 Hz),7.20-7.32 (m, 5H)

¹³C-NMR (δ (ppm), CDCl₃): 22.3, 25.1, 30.9, 36.4, 50.2, 51.6, 57.5,58.5, 126.8, 128.2, 128.7, 139.6, 173.3

MS (CI, i-C₄H₁₀) m/z: 248 (MH⁺)

Elemental analysis; Calcd.: C, 72.84%; H, 8.56%; N, 5.66% Found: C,72.50%; H, 8.73%; N, 5.66%

Physical properties of the (R)-N-benzylhomopipecolic acid were asfollows.

¹H-NMR (δ (ppm), CD₃OD): 1.55-2.15 (m, 6H), 2.96 (dd, 1H, J=6.8, 17.6Hz), 3.03 (m, 1H), 3.22 (m, 1H), 3.14 (dd, 1H, J=4.9, 17.6 Hz), 3.71 (m,1H), 4.27 (d, 1H, J=13.7 Hz), 4.66 (d, 1H, J=13.7 Hz), 7.46-7.59 (m, 5H)

MS (CI, i-C₄H₁₀) m/z: 234 (MH⁺)

Incidentally, absolute configuration of the optically activeN-benzylhomopipecolic acid was determined as follows. That is, 100 mg ofthe optically active N-benzylhomopipecolic acid having an optical purityof 96.7% ee obtained by the operation of Example 1 was dissolved in 2 mLof methanol, 23.2 mg of 20% palladium/carbon powder was added to thesolution, and the mixture was reacted at room temperature whilestirring. After 1 hour, the reaction mixture was filtered through Celite(No. 545), and washed with 5 ml of methanol. The resulting filtrate wasconcentrated under reduced pressure to obtain an oily substance. Thisoily substance was purified by silica gel column chromatography (WakogelC-200 (trade name), chloroform/methanol=98/2 to 0/100 (volume ratio)) toobtain 51.3 mg (Isolated yield based on optically activeN-benzylhomopipecolic acid=85.0%) of optically active homopipecolicacid. Absolute configuration was determined by comparing the specificrotatory power ([α]²³ _(D)−54.8° (C 1.30, H₂O)) of the resultingoptically active homopipecolic acid and a sign (literal value [α]²⁵_(D)+22.1° (C 0.6, H₂O)) of the specific rotatory power of(R)-homopipecolic acid described in Synth. Comm., 7 (4), 239 (1977).

Example 15 Syntheses of Methyl (S)-N-benzylhomopipecolate and(R)-N-benzylhomopipecolic Acid

To a mixed solvent of 1 mL of cyclohexane and 1 mL of water was added100 mg of methyl (±)-N-benzylhomopipecolate, and the mixture wasmaintained at 30° C. To the resulting mixture was added 10 mg of lipase(CAL; available from Roche, Chirazyme L-2 (trade name)) originated fromCandida antarctica at the same temperature, and the mixture was reactedat 30° C. while stirring. After 7 hours, at the time when the conversionrate of the starting materials reached 50.1%, 2 mol/L of hydrochloricacid was added to the reaction mixture to adjust a pH to 1, filteredthrough Celite (No. 545), and washed with 5 ml of methanol. To theresulting filtrate was added 20 mol of chloroform, and the product andthe starting materials were extracted. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, and afterfiltration, the organic layer was concentrated under reduced pressure toobtain an oily substance. The resulting oily substance was purified bysilica gel column chromatography (Wakogel C-200 (trade name),chloroform/methanol=98/2 to 80/20 (volume ratio)) to obtain 42.2 mg(Isolated yield based on methyl (±)-N-benzylhomopipecolate=42.2%) ofmethyl (S)-N-benzylhomopipecolate and 39.7 mg (Isolated yield based onmethyl (±)-N-benzylhomopipecolate=41.3%) of (R)-N-benzylhomopipecolicacid.

When the optical purify of methyl (S)-N-benzylhomopipecolate wasmeasured by using high performance liquid chromatography that uses anoptically active column, it was 99.1% ee.

When the optical purify of (R)-N-benzylhomopipecolic acid was measuredby using high performance liquid chromatography that uses an opticallyactive column, it was 98.8% ee.

Analytical conditions of high performance liquid chromatography;

Methyl N-benzylhomopipecolate

Column: chiral pack AS (0.46 cmΦ×25 cm, available from DAICEL CHEMICALINDUSTRIES, LTD.)

Solvent: hexane/isopropyl alcohol (=9/1 (volume ratio))

Flow rate: 0.5 ml/min

Temperature: 30° C.

N-benzylhomopipecolic Acid

Column: chiral CD-Ph (0.46 cmΦ×25 cm, available from SHISEIDO CO., LTD.)

Solvent: acetonitrile/water (=1/9 (volume ratio)) Potassium dihydrogenphosphate 40 mM pH 3.5

Flow rate: 0.5 ml/min

Temperature: 25° C.

Incidentally, spectrum data were the same as those obtained in Example1.

Example 15 Syntheses of (R)-N-benzylhomopipecolic Acid and Methyl(S)-N-benzylhomopipecolate

To a mixed solvent of 4 mL of cyclohexane and 4 mL of water was added800 mg of methyl (±)-N-benzylhomopipecolate, and the mixture wasmaintained at 30° C. To the resulting mixture was added 40 mg of lipase(CAL; available from Roche, Chirazyme L-2 (trade name)) originated fromCandida antarctica at the same temperature, and the mixture was reactedat 30° C. while stirring. After 5 hours, at the time when the conversionrate of the starting materials reached 49.7%, 2 mol/L of hydrochloricacid was added to the reaction mixture to adjust a pH to 1, filteredthrough Celite (No. 545), and washed with 5 ml of methanol. To theresulting filtrate was added 30 mol of chloroform, and the product andthe starting materials were extracted. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, and afterfiltration, the organic layer was concentrated under reduced pressure toobtain an oily substance. The resulting oily substance was purified bysilica gel column chromatography (Wakogel C-200 (trade name),chloroform/methanol=98/2 to 80/20 (volume ratio)) to obtain 359 mg(Isolated yield based on methyl (±)-N-benzylhomopipecolate=43.1%) ofmethyl (S)-N-benzylhomopipecolate and 314 mg (Isolated yield based onmethyl (±)-N-benzylhomopipecolate=40.8%) of (R)-N-benzylhomopipecolicacid.

When the optical purify of methyl (S)-N-benzylhomopipecolate wasmeasured by using high performance liquid chromatography that uses anoptically active column, it was 95.7% ee.

When the optical purify of (R)-N-benzylhomopipecolic acid was measuredby using high performance liquid chromatography that uses an opticallyactive column, it was 96.7% ee.

Analytical conditions of high performance liquid chromatography;

Methyl N-benzylhomopipecolate

Column: chiral pack AS (0.46 cmΦ×25 cm, available from DAICEL CHEMICALINDUSTRIES, LTD.)

Solvent: hexane/isopropyl alcohol (=9/1 (volume ratio))

Flow rate: 0.5 ml/min

Temperature: 30° C.

N-benzylhomopipecolic Acid

Column: chiral CD-Ph (0.46 cmΦ×25 cm, available from SHISEIDO CO., LTD.)

Solvent: acetonitrile/water (=1/9 (volume ratio)) Potassium dihydrogenphosphate 40 mM pH 3.5

Flow rate: 0.5 ml/min

Temperature: 25° C.

Incidentally, spectrum data were the same as those obtained in Example1.

Reference Example 1 Synthesis of Methyl3-benzylamino-4-methyl-2-pentenoate

In 140 ml of methanol was dissolved 20.00 g (0.14 mol) of methyl3-oxo-4-methyl-pentanoate, then, 17.83 g (0.17 mol) of benzylamine and 4g of phosphomolybdic acid were added at room temperature, and theresulting mixture was reacted under reflux and stirring for 4.5 hours.After completion of the reaction, 300 ml of toluene and 100 ml of asaturated aqueous sodium hydrogen carbonate solution were added to thereaction mixture and the organic layer was extracted. The obtainedorganic layer was dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure to obtain an oily product. Theobtained oily product was distilled under reduced pressure to obtain26.36 g (Yield based on methyl 3-oxo-4-methylpentanoate=81%) of methyl3-benzylamino-4-methyl-2-pentenoate as an objective product.

Physical properties of the methyl 3-benzylamino-4-methyl-2-pentenoatewere as follows.

Boiling point: 130-133° C./188.6 Pa

(major isomer)

¹H-NMR (δ (ppm), CDCl₃): 1.11 (d, 6H, J=6.8 Hz), 3.21 (q, 1H, J=6.8 Hz),3.64 (s, 3H), 4.46 (d, 2H, J=6.3 Hz), 4.60 (s, 1H), 7.24-7.36 (m, 5H),9.06 (brs, 1H)

(minor isomer)

¹H-NMR (δ (ppm), CDCl₃): 1.16 (d, 3H, J=3.4 Hz), 1.19 (d, 3H, J=6.8 Hz),2.35 (qq, 3H, J=6.8 Hz, 3.4 Hz), 3.65 (s, 3H), 4.46 (d, 2H, J=6.3 Hz),4.83 (d, 1H, J=1.5 Hz), 7.24-7.43 (m, 5H)

MS (EI) m/z: 233 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 234 (MH⁺)

Reference Example 2 Synthesis of Methyl 3-benzylamino-4-methylpentanoate

In 110 ml of acetic acid was dissolved 26.00 g (0.11 mol) of methyl3-benzylamino-4-methyl-2-pentenoate, 5.33 g (0.14 mmol) of sodiumtetrahydroborate was added to the solution at the room temperature, andthe resulting mixture was reacted at the same temperature for 45 minutesunder stirring. After completion of the reaction, the obtained reactionmixture was concentrated under reduced pressure, 300 ml of ethyl acetateand 100 ml of a saturated aqueous sodium hydrogen carbonate solutionwere added thereto, and the organic layer was adjusted to a pH of 7.2with 1 mol/L of an aqueous sodium hydroxide solution, and the organiclayer was extracted. The obtained organic layer was dried over anhydrousmagnesium sulfate, and after filtration, the organic layer wasconcentrated under reduced pressure to obtain an oily substance. Theobtained oily product was distilled under reduced pressure to obtain21.54 g (Isolated yield based on methyl3-benzylamino-4-methyl-2-pentenoate=82%) of methyl3-benzylamino-4-methylpentanoate as an objective product.

Physical properties of the methyl 3-benzylamino-4-methylpentanoate wereas follows.

Boiling point: 113-115° C./226.6 Pa

¹H-NMR (δ (ppm), CDCl₃): 0.90 (d, 3H, J=6.8 Hz), 0.92 (d, 3H, J=6.8 Hz),1.88 (dqq, 1H, J=4.9, 6.8, 6.8 Hz), 2.34 (dd, 1H, J=8.3, 15.1 Hz), 2.45(dd, 1H, J=4.8, 15.1 Hz), 2.89 (ddd, 1H, J=4.8, 4.9, 8.3 Hz), 3.66 (s,3H), 3.77 (s, 2H), 7.20-7.34 (m, 5H)

¹³C-NMR (δ (ppm), CDCl₃): 17.5, 18.8, 21.3, 30.2, 35.5, 51.2, 51.7,59.3, 127.2, 128.4, 139.6, 173.4, 175.9

MS (CI, i-C₄H₁₀) m/z: 236 (MH⁺)

Elemental analysis; Calcd.: C, 71.45%; H, 9.00%; N, 5.95% Found: C,71.15%; H, 9.21%; N, 5.88%

Reference Example 3 Synthesis of N-benzyl-2-carbomethoxymethylpiperidine

In 13 ml of acetonitrile was dissolved 1.0 g (5.16 mmol) of2-carbomethoxymethylpiperidine hydrochloride, and 1.77 ml (12.72 mmol)of triethylamine and 0.76 ml (6.36 mmol) of benzyl bromide were added tothe solution at room temperature, and the resulting mixture was reactedat the same temperature under stirring for 5 hours. After completion ofthe reaction, the obtained reaction mixture was filtered and thenconcentrated under reduced pressure, then, 25 ml of ethyl acetate and 15ml of a saturated aqueous sodium hydrogen carbonate solution were addedto the residue and the organic layer was extracted. The obtained organiclayer was washed with 15 ml of a saturated aqueous sodium hydrogencarbonate solution, and saturated saline solution, dried over anhydrousmagnesium sulfate, then, filtered and the filtrate was concentratedunder reduced pressure to obtain 0.97 g of an oily substance. Theresulting oily substance was purified by silica gel columnchromatography (Wakogel C-200 (trade name), n-hexane/ethylacetate=4/1(volume ratio)) to obtain 0.75 g (Isolated yield based on2-carbomethoxymethylpiperidine hydrochloride=59%) ofN-benzyl-2-carbomethoxymethylpiperidine.

Incidentally, the racemic 2-carboxymethylpiperidine hydrochloride usedin this example was synthesized after synthesizing2-carboxymethylpiperidine according to the method described in Can. J.Chem., 53, 41 (1975), then, subjecting to esterification reactionaccording to the reaction described in Can. J. Chem., 65, 2722 (1987).

Physical properties of the N-benzyl-2-carbomethoxymethylpiperidine wereas follows.

¹H-NMR (δ (ppm), CDCl₃): 1.38-1.64 (m, 6H), 2.18 (ddd, 1H, J=3.9, 7.8,16.1 Hz), 2.45 (dd, 1H, J=7.8, 14.7 Hz), 2.62 (ddd, 1H, J=2.9, 3.9, 16.1Hz), 2.72 (dd, 1H, J=4.9, 14.7 Hz), 2.97 (dddd, 1H, J=4.4, 4.9, 7.8, 7.8Hz), 3.35 (d, 1H, J=13.7 Hz), 3.67(s, 3H), 3.80 (d, 1H, J=13.7 Hz),7.20-7.32 (m, 5H)

¹³C-NMR (δ (ppm), CDCl₃): 22.3, 25.1, 30.9, 36.4, 50.2, 51.6, 57.5,58.5, 126.8, 128.2, 128.7, 139.6, 173.3

MS (EI) m/z: 247 (M⁺)

MS (CI, i-C₄H₁₀) m/z: 248 (MH⁺)

Elemental analysis; Calcd.: C, 72.84%; H, 8.56%; N, 5.66% Found: C,72.50%; H, 8.73%; N, 5.66%

Utilizability in Industry

According to the present invention, an industrially suitable process forpreparing an optically active β-amino acid and an optically activeβ-amino acid ester or an N-substituted 2-homopipecolic acid and anoptically active N-substituted 2-homopipecolic acid ester can beprovided, which can give an optically active ((R) or (S))-N-substitutedβ-amino acid and an optically active ((S) or (R))-N-substituted β-aminoacid alkyl ester or an optically active ((R) or (S))-N-substituted2-homopipecolic acid and an optically active ((R) or (S))-N-substituted2-homopipecolic acid ester simultaneously with a high yield and highselectivity from an N-substituted β-amino acid alkyl ester or anN-substituted 2-homopipecolic acid ester (racemic mixture) with a simpleand easy process.

1. A process for preparing an optically active β-amino acid and anoptically active β-amino acid ester or N-substituted 2-homopipecolicacid and an optically active N-substituted 2-homopipecolic acid esterwhich comprises selectively hydrolyzing an enantiomer of racemic mixtureof an N-substituted β-amino acid alkyl ester or an N-substituted2-homopipecolic acid ester represented by the formula (I):

wherein Ar represents a substituted or unsubstituted aryl group, R¹represents a substituted or unsubstituted alkyl group, alkenyl group, asubstituted or unsubstituted aralkyl group or a substituted orunsubstituted aryl group, R² represents a hydrogen atom, R³ and R⁴ eachindependently represent a hydrogen atom, a substituted or unsubstitutedalkyl group or a substituted or unsubstituted aryl group, R⁵ representsa substituted or unsubstituted alkyl group, also, R¹ and R² may bebonded to form a ring, in the presence of a hydrolase to form anoptically active ((R) or (S))-N-substituted-β-amino acid or an opticallyactive ((R) or (S))-N-substituted-2-homopipecolic acid represented bythe formula (II)

wherein Ar, R¹, R², R³ and R⁴ have the same meanings as defined above,and simultaneously to obtain an unreacted optically active ((S) or(R))-N-substituted-β-amino acid alkyl ester or an unreacted opticallyactive ((S) or (R))-N-substituted-2-homopipecolic acid ester representedby the formula (III):

wherein Ar, R¹, R², R³, R⁴ and R⁵ have the same meanings as definedabove, provided that it has a reverse steric absolute configuration tothat of the compound represented by the formula (II).
 2. The preparationprocess according to claim 1, wherein the hydrolase is a protease, anesterase or a lipase.
 3. The preparation process according to claim 1,wherein the hydrolase is a lipase originated from Candida antarctica. 4.The preparation process according to claim 1, wherein the hydrolysis iscarried out in an aqueous solvent, in a buffer solvent, in a 2-phasesolvent of an organic solvent and water, or in a 2-phase solvent of anorganic solvent and a buffer.
 5. The preparation process according toclaim 4, wherein the organic solvent is an aliphatic hydrocarbon, anaromatic hydrocarbon or an ether, or a mixed solvent thereof.
 6. Thepreparation process according to claim 1, wherein the compoundrepresented by the formula (I) is a N-substituted-β-amino acid alkylester represented by the following formula (I-a):

wherein Ar, R¹, R², R³, R⁴ and R⁵ have the same meanings as definedabove, and the compounds represented by the formula (II) and the formula(III) are an optically active ((R) or (S))-N-substituted-β-amino acidand an optically active ((S) or (R))-N-substituted-β-amino acid alkylester represented by the following formulae (II-a) and (III-a):

wherein Ar, R¹, R³, R⁴ and R⁵ have the same meanings as defined above.7. The preparation process according to claim 1, wherein the compoundrepresented by the formula (I) is an N-substituted-2-homopipecolic acidester represented by the following formula (I-b):

wherein Ar, R³, R⁴ and R⁵ have the same meanings as defined above, andthe compounds represented by the formula (II) and the formula (III) arean optically active ((R) or (S))-N-substituted-2-homopipecolic acid andan optically active ((S) or (R))-N-substituted-2-homopipecolic acidester represented by the following formulae (II-b) and (III-b):

wherein Ar, R³, R⁴ and R⁵ have the same meanings as defined above. 8.The preparation process according to claim 1, wherein each of theoptically active ((R) or (S))-N-substituted-β-amino acid or theoptically active ((R) or (S))-N-substituted-2-homopipecolic acidrepresented by the formula (II):

wherein Ar, R¹, R², R³ and R⁴ have the same meanings as defined above,and the unreacted optically active ((S) or (R))-N-substituted-β-aminoacid alkyl ester or the unreacted optically active ((S) or(R))-N-substituted-2-homopipecolic acid ester represented by the formula(III):

wherein Ar, R¹, R², R³, R⁴ and R⁵ have the same meanings as definedabove, provided that it has a reverse steric absolute configuration tothat of the compound represented by the formula (II), formed byhydrolysis reaction, is isolated from the mixture thereof.
 9. Thepreparation process according to claim 7, wherein the optically active((R) or (S))-N-substituted-β-amino acid represented by the formula(II-a) is optically active N-substituted-α-amino acid represented by theformula (IV-a):

wherein Ar, R³ and R⁴ have the same meanings as defined above, and theunreacted optically active ((S) or (R))-N-substituted-2-β-amino acidester is an optically active N-substituted-β-amino acid esterrepresented by the formula (V-a):

wherein Ar, R³, R⁴ and R⁵ have the same meanings as defined above. 10.The preparation process according to claim 7, wherein the opticallyactive ((R) or (S))-N-substituted-2-homopipecolic acid represented bythe formula (I-b) is an optically active(R)-N-substituted-2-homopipecolic acid represented by the formula(IV-b):

wherein Ar, R³ and R⁴ have the same meanings as defined above, and theunreacted optically active ((S) or (R))-N-substituted-2-homopipecolicacid ester represented by the formula (III-b) is an optically active(S)-N-substituted-2-homopipecolic acid ester represented by the formula(V-b):

wherein Ar, R³, R⁴ and R⁵ have the same meanings as defined above. 11.The preparation process according to claim 2, wherein the hydrolase is alipase originated from Candida antarctica.